WO2010016936A1

WO2010016936A1 - Pharmaceutical compositions of analogues of glucose-dependent insulinotropic polypeptide

Info

Publication number: WO2010016936A1
Application number: PCT/US2009/004545
Authority: WO
Inventors: Zheng Xin Dong; Jundong Zhang
Original assignee: Ipsen Pharma SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2008-08-07
Filing date: 2009-08-07
Publication date: 2010-02-11
Anticipated expiration: 2011-02-07

Abstract

The present invention relates to improvements in compositions containing an analogue of glucose-dependent insulinotropic polypeptide or pharmaceutical salts thereof, and the use of such compositions for treatment of GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity. In particular, the present invention relates to a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GIP peptide" or "GIP compound"), and a divalent metal or divalent metal salt component such as ZnCl₂or ZnAc₂, in which the clear aqueous solution of the GIP peptide precipitates in vivo at physiological pH to form an in situ deposit that is slowly dissolved and released into the body fluid and bloodstream.

Description

PHARMACEUTICAL COMPOSITIONS OF ANALOGUES OF GLUCOSE-DEPENDENT

INSULINOTROPIC POLYPEPTIDE

BACKGROUND QF THE INVENTION The present invention relates to improvements in compositions containing an analogue of glucose-dependent insulinotropic polypeptide or pharmaceutical salts thereof, and the use of such compositions for treatment of GIP -receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity. In particular, the present invention relates to a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GIP peptide" or "GIP compound"), and a divalent metal or divalent metal salt component such as ZnCl₂ or ZnAc₂, in which the clear aqueous solution of the GIP peptide precipitates in vivo at physiological pH to form an in situ deposit that is slowly dissolved and released into the body fluid and bloodstream. Glucose-dependent insulinotropic polypeptide ("GIP", also known as "gastric inhibitory polypeptide") is a 42 -residue peptide secreted by enteroendorine K-cells of the small intestine into the bloodstream in response to oral nutrient ingestion. GIP inhibits the secretion of gastric acid, and it has been shown to be a potent stimulant for the secretion of insulin from pancreatic beta cells after oral glucose ingestion (the "incretin effect") (Creutzfeldt, W., et al, 1979, Diabetologia, 16:75-85). Insulin release induced by the ingestion of glucose and other nutrients is due to both hormonal and neural factors (Creutzfeldt, W., et al, 1985, Diabetologia, 28:565-573). Several gastrointestinal regulatory peptides have been proposed as incretins, and among these candidates, only GIP and glucagon-like peptide 1 ("GLP-I") appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (Nauck, et al., 1989, J. CHn. Endorinol. Metab., 69:654- 662). It has been shown that the combined effects of GIP and GLP-I are sufficient to explain the full incretin effect of the enteroinsular axis (Fehmann, H. C, et al., 1989, FEBS Lett., 252:109-112).

As is well known to those skilled in the art, the known and potential uses of GIP are varied and multitudinous. Thus, the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as GDP itself. These varied uses of GIP may be summarized as follows: treating a disease selected from the group consisting of type 1 diabetes, type 2 diabetes (Visboll, T., 2004, Dan. Med. Bull., 51 :364-70), insulin resistance (WO 2005/082928), obesity (Green, B. D., et al, 2004, Current Pharmaceutical Design, 10:3651-3662), metabolic disorder (Gault, V. A., et al, 2003, Biochem. Biophys. Res. Commun., 308:207-213), central nervous system disease, neurodegenerative disease, congestive heart failure, hypoglycemia, and disorders wherein the reduction of food intake and weight loss are desired. In pancreatic islets, GIP not only enhances insulin secretion acutely, but it also stimulates insulin production through enhancement of proinsulin transcription and translation (Wang, et al, 1996, MoI Cell Endocrinol., 116:81-87) and enhances the growth and survival of pancreatic beta cells (Trumper, et al, 2003, Diabetes, 52:741-750). In addition to effects on the pancreas to enhance insulin secretion, GIP also has effects on insulin target tissues directly to lower plasma glucose: enhancement of glucose uptake in adipose (Eckel, et al, 1979, Diabetes, 28: 1141-1142) and muscle (O'Harte, et al, 1998, J.

Endocrinol, 156:237-243), and inhibition of hepatic glucose production (Elahi, D., et al, 1986, Can. J. Physiol Pharmacol, 65: Al 8).

In addition, a GIP receptor antagonist in accordance with the present invention inhibits, blocks or reduces glucose absorption from the intestine of an animal. In accordance with this observation, therapeutic compositions containing GIP antagonists may be used in patients with non- insulin dependent diabetes mellitus to improve tolerance to oral glucose in mammals, such as humans, to prevent, inhibit or reduce obesity by inhibiting, blocking or reducing glucose absorption from the intestine of the mammal.

The use of unmodified GIP as a therapeutic, however, is limited by the short in vivo half-life of about 2 minutes (Said and Mutt, 1970, Science, 169:1217-1218). In serum, both incretins, GIP and GLP-I, are degraded by dipeptidyl peptidase IV ("DPPIV"). Improving the stability of GIP to proteolysis not only maintains the activity of GIP at its receptor but, more importantly, prevents the production of GEP fragments, some of which act as GIP receptor antagonists (Gault, et al, 2002, J. Endocrinol, 175:525-533). Reported modifications have included protection of the N-terminus of GIP from proteolysis by DPPIV through modification of the N-terminal tyrosine (O'Harte, et al, 2002, Diabetologia, 45: 1281-1291), mutation of the alanine at position 2 (Hinke, et al, 2002, Diabetes, 51 :656-661), mutation of glutamic acid at position 3 (Gault, et al, 2003, Biochem. Biophys. Res. Commun., 308:207-213), and mutation of alanine at position 13 (Gault, et al, 2003, Cell Biol. International, 27:41-46), The following patent applications have been filed related to the effects of GIP analogues on the function of various target organs and their potential use as therapeutic agents:

PCT publication WO 00/58360 discloses peptidyl analogues of GIP which stimulate the release of insulin. In particular, this application discloses specific peptidyl analogues comprising at least 15 amino acid residues from the N-terminal end of GIP(l-42) (SEQ ID NO:1), e.g., an analogue of GIP containing exactly one amino acid substitution or modification at positions 1, 2 and 3, such as (Pro³)GIP(l-42) (SEQ ID NO:9).

PCT publication WO 98/24464 discloses an antagonist of GIP consisting essentially of a 24- amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP, a method of treating non-insulin dependent diabetes mellitus and a method of improving glucose tolerance in a non-insulin dependent diabetes mellitus patient. PCT publication WO 03/082898 discloses C-terminal truncated fragments and N-terminal modified analogues of GIP, as well as various GIP analogues with a reduced peptide bond or alterations of the amino acids close to the DPPIV-specific cleavage site. This application further discloses analogues with different linkers between potential receptor binding sites of GIP. The compounds of this application are alleged to be useful in treating GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.

There exists a need for improved GIP formulations that provide sustained release profile upon subcutaneous injection. Ideally, such improved sustained release GIP formulations comprise novel analogues of GIP as illustrated herein which are stable in formulation and have long plasma half-life in vivo resulting from decreased susceptibility to proteolysis and decreased clearance while maintaining binding affinity to a GIP receptor to elicit respective agonistic or antagonistic effects. Moreover, among other therapeutic effects of the compounds of the present invention as illustrated herein, tighter control of plasma glucose levels may prevent long-term diabetic complications, thereby providing an improved quality of life for patients.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof. Particularly preferred are the following novel analogues of GIP:

Example 1 : (A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO: 15);

Example 2: (A5c"' ⁴⁰)hGIP(l-42)-OH (SEQ ID NO: 16);

Example 3: (A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO: 17);

Example 4: (A5c", Asn⁴³)hGIP(l-43)-OH (SEQ ID NO: 18);

Example 5: (Aib¹³, Asp⁴³)hGIP(l-43)-NH2 (SEQ ID NO: 19);

Example 6: (Aib¹³, NIe¹⁴, A5c⁴⁰)hGIP(l-42)-OH (SEQ ID NO:20);

Example 7: (Aib¹³, A5c⁴⁰)hGIP(l-42)-OH (SEQ ID NO:21);

Example 8: (A5c", Ala⁴³)hGIP(l-43)-OH (SEQ ID NO:22);

Example 9: (Aib¹³, NIe¹⁴, Phe⁴³)hGIP(l-43)-OH (SEQ ID NO:23);

Example 10: (A5c^π, Thr⁴³)hGIP(l-43)-OH (SEQ ID NO:24); Example 11: (AOc¹¹' ^{14 4l})hGIP(l-42)-OH (SEQ ID NO:25);

Example 12: (Aib¹³, Trp⁴³)hGIP(l-43)-OH (SEQ ID NO:26);

Example 13: (A5cⁿ, Ado⁴³)hGIP(l-43)-OH (SEQ ID NO:27);

Example 14: (A6c"' ^l4' ⁴⁰)hGIP(l-42)-OH (SEQ ID NO:28);

Example 15: [A6c⁷, Cys(Psu)⁴²]hGIP(l-42)-OH (SEQ ID NO:29); Example 16: (A6c⁷' ^4I)hGIP(l-42)-OH (SEQ ID NO:30);

Example 17: (A6c⁷' ⁴¹, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:31); Example 18: [A6c⁷, Om³⁵(N-C(O)-(CH₂)₁₂-CH₃)]hGIP(l-42)-OH (SEQ ID NO:32);

Example 19: [A6c⁷, Orn³¹(N-C(O)-(CH₂)₁₂-CH₃)]hGIP(l-42)-OH (SEQ ID NO:33);

Example 20: (A5cⁿ' ¹⁴, His⁴³)hGD?(l-43)-OH (SEQ ID NO:34);

Example 21 : (A5cⁿ, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:35); Example 22: [A5c^π, Orn³²(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:36);

Example 23: [A5c^π, Om³³(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:37);

Example 24: [A5cⁿ, Om⁴³(N-C(O)-(CH₂)₁₄-CH₃)]hGIP(l-43)-OH (SEQ ID NO:38);

Example 25: [A5cⁿ, Cys³²(succinimide-N-(CH₂)₁₅-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:39);

Example 26: [A5c^π, Cys³³(succinimide-N-(CH₂)₁₅-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:40); Example 27: [A5c^π, Cys⁴³(succinimide-N-(CH₂)₁₅-CH₃)]hGIP(l-43)-OH (SEQ ID NO:41);

Example 28: (4HpPa¹, Aib², A5c⁷, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:42);

Example 29: (4HpPa¹, Aib²' ^π, Nle^I4)hGIP(l -3O)-NH₂ (SEQ ID NO:43);

Example 30: (4HpPa¹, Aib², A5c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO:44);

Example 31:

-3 O)-NH₂ (SEQ ID NO:45); Example 32: (4Hppa', Aib², Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:46);

Example 33: (4Hppa\ Aib²)hGIP(l -3O)-NH₂ (SEQ ID NO:47);

Example 34: (4Hppa\ 4Hyp³, A6c⁷)hGIP(l-42)-OH (SEQ ID NO:48);

Example 35: (4HpPa¹, hPro³, A6c⁷)hGIP(l-42)-OH (SEQ ID NO:49);

Example 36: (4HpPa¹, Aib², hPro³, Nle'⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:50); Example 37: (His¹, Aib^{2 13}, Nle¹⁴)hGIP(l-42)-OH (SEQ DD NO:51);

Example 38: (3,5Br-TyT¹, Aib²' ¹³, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:52);

Example 39: (His¹, Aib², A5c^u, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:53);

Example 40: (3,5Br-TyT¹, Aib², A5c", Nle^M)hGIP(l-42)-OH (SEQ ID NO:54);

Example 41 : (3Cl-TyT¹, Aib², A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:55); Example 42: (3Br-Tyr", Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:56);

Example 43: (31-Tyr¹, Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:57);

Example 44: (3,51-Tyr¹, Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:58);

Example 45: (4NH₂-PlIe¹, Aib², A5c^u, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:59);

Example 46: (hTyr¹, Aib², A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:60); Example 47: (Cpa¹, Aib², A5cⁿ, Nle¹⁴)hGIP(l-42)-OH (SEQ ID N0:61);

Example 48: (4NH₂CH₂-PlIe¹, Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ DD NO:62);

Example 49: (3,4,5F-PlIe¹, Aib², A5c", Nle'⁴)hGIP(l-42)-OH (SEQ ED NO:63);

Example 50: (3F-PlIe¹, Aib², A5c^π, Nle^M)hGIP(l-42)-OH (SEQ ID NO:64);

Example 51 : (3,4F-Phe', Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:65); Example 52: (3,5F-Phe', Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:66);

Example 53: (3OH-Phe', Aib², A5c"'⁴¹)hGIP(l-42)-OH (SEQ DD NO:67);

Example 54: (3OH-Tyr', Aib², A5c^{11 41})hGIP(l-42)-OH (SEQ DD NO:68); Example 55: (3MeO-TyT¹, Aib², A5c^π'⁴¹)hGff(l-42)-OH (SEQ ID NO:69);

Example 56: (Tyr(Ac)¹, Aib², A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO:70);

Example 57: (2,6Me-TyT¹, Aib², A5c^{1 M1})hGD^>(l-42)-OH (SEQ ID NO:71);

Example 58: (Tyr(Me)\ Aib², A5c"^{> 41})hGIP(l-42)-OH (SEQ ID NO:72);

Example 59: (4F-Phe', Aib², A5c^π' ⁴¹)hGIP(l-42)-OH (SEQ DD NO:73);

Example 60: (4PaI¹, Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ ID NO:74);

Example 61 : (3PaI¹, Aib², A5c^u'⁴¹)hGIP(l-42)-OH (SEQ ID NO:75);

Example 62: (Taz¹, Aib², A5c^{11 41})hGIP(l-42)-OH (SEQ DD NO:76);

Example 63: (3NO₂-TyT¹, Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ ED NO:77);

Example 64: (3TW¹, Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ ID NO:78);

Example 65: (4CN-Phe\ Aib², A5c^π' ⁴¹)hGIP(l-42)-OH (SEQ DD NO:79);

Example 66: (3F-TyT¹, GIy², A5c^π' ⁴⁰)hGIP(l-42)-OH (SEQ DD NO:80);

Example 67: [TyT¹^-(CH₂-NH)GIy², A5c^π' ⁴¹JhGIP(I -42)-OH (SEQ DD NO:81);

Example 68: (3F-PlIe¹, Aib², A5c^π' ⁴¹)hGD⁾(l-42)-OH (SEQ DD NO:82);

Example 69: (3C1-Phe', Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ DD NO:83);

Example 70: (3Br-Phe', Aib², A5c^u' ⁴¹)hGD⁾(l-42)-OH (SEQ DD NO:84);

Example 71 : (3Cl-TyT¹, Aib², A5c^{11 41})hGD^>(l-42)-OH (SEQ DD NO:85);

Example 72: (3Br-TyT¹, Aib², A5c^u- ⁴¹)hGD^>(l-42)-OH (SEQ DD NO:86);

Example 73: (β-Tyr¹, Aib², A5c^{l ll 41})hGIP(l-42)-OH (SEQ DD NO:87);

Example 74: Aib², A5c¹¹' ⁴¹)hGE⁾(l-42)-OH (SEQ DD NO:88);

Example 75: (2F-Tyτ', Aib², A5c^{11> 41})hGD^>(l-42)-OH (SEQ DD NO:89);

Example 76: (αMe-Tyr¹, Aib², A5c^{11 41})hGD^>(l-42)-OH (SEQ DD NO:90);

Example 77: (3NH₂-TyT¹, Aib², A5c^π' ⁴¹)hGIP(l-42)-OH (SEQ DD NO:91);

Example 78: (2PaI¹, Aib², A5c"' ⁴¹)hGIP(l-42)-OH (SEQ DD NO:92);

Example 79: [3(HO-CH₂)TyT¹, Aib², A5c" ⁴¹]hGD^>(l-42)-OH (SEQ DD NO:93);

Example 80: (2,6Me-TyT¹, Aib², A5c^π, His⁴³)hGD^>(l-43)-OH (SEQ DD NO:94);

Example 81 : (2,6Me-TyT¹, Aib², A5c^{Ul 14}, His⁴³)hGD^>(l-43)-OH (SEQ DD NO:95);

Example 82: (2,6Me-TyT¹, Aib², A5c^u, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ DD NO:96);

Example 83: (Ac-A6c⁷)hGIP(7-42)-OH (SEQ ID NO:97);

Exampl3 84: [Ac-A6c⁷, Cys(Psu)⁴⁰]hGD^>(7-42)-OH (SEQ DD NO:98);

Example 85: [Ac-A6c⁷, Cys(Psu)³⁹]hGD^>(7-42)-OH (SEQ DD NO:99);

Example 86: [Ac-A6c⁷, Cys(Psu)³⁸]hGIP(7-42)-OH (SEQ DD NO: 100);

Example 87: [Ac-A6c⁷, Cys(Psu)³⁶]hGπ^>(7-42)-OH (SEQ DD NO: 101);

Example 88: [Ac-A6c⁷, Cys(Psu)³⁵]hGD^>(7-42)-OH (SEQ DD NO: 102);

Example 89: [Ac-A6c⁷, Cys(Psu)³⁴]hGff(7-42)-OH (SEQ DD NO: 103);

Example 90: [Ac-A6c⁷, Cys(Psu)³³]hGD^>(7-42)-OH (SEQ DD NO: 104);

Example 91 : [Ac-A6c⁷, Cys(Psu)³²]hGIP(7-42)-OH (SEQ DD NO: 105); Example 92: [Ac-A6c⁷, Cys(Psu)³¹]hGIP(7-42)-OH (SEQ ID NO: 106);

Example 93 : [Ac-A6c⁷, Cys(Psu)³⁷]hGIP(7-42)-OH (SEQ ID NO: 107);

Example 94: [Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂)_l2-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 108);

Example 95: [Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO:109); Example 96: [A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 110);

Example 97: [CH₃-(CH₂)₈-C(O)-A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 111);

Example 98 [Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 112);

Example 99: [A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-0H (SEQ ID NO: 113); Example 100: [CH₃-(CH₂)₄-C(O)-A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 114);

Example 101 : [Ac-A6c⁷, Orn³⁴(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 115);

Example 102: [A6c⁷, Orn³⁴(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 116);

Example 103: [CH₃-(CH₂)₈-C(O)-A6c⁷, Orn³⁴(N-C(O)-(CH₂)_g-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 117);

Example 104: [Ac-A6c⁷, Cys(Hsu)³¹]hGIP(7-42)-OH (SEQ ID NO: 118);

Example 105: [A6c⁷, Cys(Hsu)³¹]hGIP(7-42)-OH (SEQ ID NO:119);

Example 106: (Ac-A6c⁷, 2Nal³¹)hGIP(7-42)-OH (SEQ ID NO: 120);

Example 107: (Ac-A6c⁷, D-2Nal^3I)hGIP(7-42)-OH; Example 108: (Ac-4Hyp³, A6c⁷)hGIP(3-42)-OH (SEQ ID NO: 121);

Example 109: (Ac-A6c⁷, Gln⁴³)hGIP(7-43)-OH (SEQ ID NO: 122);

Example 110: [Ac-A6c⁷, Cys(Psu)³¹]hGIP(7-34)-NH₂ (SEQ ID NO: 123);

Example 111 : [Ac-A6c⁷, Cys(Psu)³¹]hGIP(7-31)-NH₂ (SEQ ID NO: 124);

Example 112: [Ac-Phe⁶, A6c⁷, Cys(Psu)³¹]hGIP(6-42)-OH (SEQ ID NO: 125); Example 113: [A6c⁷, Cys(Psu)³¹]hGIP(6-42)-OH (SEQ DD NO: 126);

Example 114: (Ac-Phe⁶, A6c⁷)hGIP(6-30)-NH₂ (SEQ ID NO: 127);

Example 115: [Ac-Phe⁶, A6c⁷, Cys(Psu)^3l]hGIP(6-31)-NH₂ (SEQ ID NO: 128);

Example 116: [A6c⁷, Cys(Psu)³¹]hGIP(6-31)-NH₂ (SEQ ID NO:129);

Example 117: (A5c⁷, Nle^l4)hGIP(6-30)-NH₂ (SEQ ID NO: 130); Example 118: (A6c⁷, Nle¹⁴)hGD?(6-30)-NH₂ (SEQ ID NO: 131);

Example 119: (Aib¹¹, Nle¹⁴)hGIP(6-30)-NH₂ (SEQ ID NO: 132);

Example 120: [Ac-Asp⁹, Cys(Psu)³³]hGD?(9-42)-OH (SEQ ID NO: 133);

Example 121 : [Orn^3l(N-C(O)-(CH₂)₈-CH₃)]hGIP(8-42)-OH (SEQ DD NO: 134);

Example 122: [Chc-Ser⁸, Cys(Psu)³¹]hGIP(8-42)-OH (SEQ ID NO: 135); Example 123: [CH₃-(CH₂)₄-C(O)-Ser⁸, Cys(Psu)³¹]hGIP(8-42)-OH (SEQ ID NO: 136);

Example 124: (4Hppa², 4Hyp³, A6c⁷)hGIP(2-42)-OH (SEQ ID NO: 137);

Example 125: (4Hppa², Pro³, Nle^M)hGIP(2-42)-OH (SEQ ID NO: 138); Example 126: (4Hppa², Aib¹³)hGEP(2-42)-OH (SEQ ID NO: 139);

Example 127: (4Hppa², A6c¹⁴)hGIP(2-42)-OH (SEQ ID NO: 140);

Example 128: (4Hppa², A6c^π)hGIP(2-42)-OH (SEQ ID NO:141);

Example 129: (Aib²' ^u)hGIP(l-42)-OH (SEQ ED NO: 142); Example 130: (Aib²'⁹)hGEP(l-42)-OH (SEQ ID NO:143);

Example 131 : (Aib²' ⁷)hGIP( 1 -42)-OH (SEQ ID NO: 144);

Example 132: (Aib²' ⁵)hGIP(l-42)-OH (SEQ ID NO: 145);

Example 133: (Aib², A5c⁵)hGC?(l -42)-OH (SEQ ID NO: 146);

Example 134: (Aib², A5c⁷)hGEP(l -42)-OH (SEQ ID NO: 147); Example 135: (Aib², A5c¹²)hGIP(l-42)-OH (SEQ ID NO:148);

Example 136: (Aib²' ¹²)hGIP(l-42)-OH (SEQ ID NO: 149);

Example 137: (Aib²' >GIP(l-42)-OH (SEQ ID NO: 150);

Example 138: (Aib²'⁴)hGEP(l-42)-OH (SEQ ID NO:151);

Example 139: (Aib², A5c⁵)hGIP(l -3O)-NH₂ (SEQ ID NO:152); Example 140: (Aib², A5c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO:153);

Example 141 : (Aib², A5c¹²)hGEP(l -3O)-NH₂ (SEQ ID NO:154);

Example 142: (Aib²' ⁴)hGEP(l -3O)-NH₂ (SEQ ID NO: 155);

Example 143: (Aib²' ⁵)hGE?(l -3O)-NH₂ (SEQ ID NO: 156);

Example 144: (Aib²' ⁷)hGEP(l -3O)-NH₂ (SEQ ID NO: 157); Example 145: (Aib²' ⁸)hGEP(l -3O)-NH₂ (SEQ ID NO: 158);

Example 146: (Aib²' >GIP( 1-3 O)-NH₂ (SEQ ID NO: 159);

Example 147: (Aib²' ^π)hGIP(l -3O)-NH₂ (SEQ ID NO: 160);

Example 148: (Aib²' ¹²)hGIP(l -3O)-NH₂ (SEQ LD NO:161);

Example 149: (Aib²' ¹³, A6c⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ED NO: 162); Example 150: (Aib²' ³¹, A6c⁷)hGEP(l-42)-OH (SEQ ED NO: 163);

Example 151 : (Aib²' ⁴¹, A6c⁷)hGEP(l-42)-OH (SEQ ID NO: 164);

Example 152: (Aib²'³¹, A6c⁷, Nle^M)hGEP(l-42)-OH (SEQ ED NO: 165);

Example 153: (Aib²'⁴¹, A6c⁷, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 166);

Example 154: (Aib², A6c⁷' ²⁶, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 167); Example 155: (Aib², A6c⁷'²⁷, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 168);

Example 156: (Aib², A6c⁷'⁴⁰, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 169);

Example 157: (Aib², A6c⁷'⁴¹, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 170);

Example 158: (Aib²' ²⁸, A6c⁷, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 171);

Example 159: (Aib², A6c⁷, NIe ¹⁴)hGEP(l -3O)-NH₂ (SEQ ED NO: 172); Example 160: (Aib², A5c⁷, Nle¹⁴)hGEP(l-30)-NH₂ (SEQ ED NO:173);

Example 161: (Aib²' ", Nle^l4)hGEP(l -3O)-NH₂ (SEQ ED NO:174);

Example 162: (A5c²' ⁷, Nle¹⁴)hGEP(l -3O)-NH₂ (SEQ ED NO: 175); Example 163: (Aib², A5c⁷' ¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 176);

Example 164: (A6c²' \ Nle^I4)hGIP(l -3O)-NH₂ (SEQ ID NO: 177);

Example 165: (Aib², A6c⁷' ¹⁷, Nle^I4)hGIP(l-42)-OH (SEQ ID NO: 178);

Example 166: (Aib^{2 11}, A6c¹⁴)hGIP(l -3O)-NH₂ (SEQ ED NO:179); Example 167: (Aib², A6c⁷' ¹⁴)hGD?(l -3O)-NH₂ (SEQ ID NO: 180);

Example 168: (A5c², Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 181);

Example 169: (Aib^{2 11}, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO: 182);

Example 170: (Aib², A6c¹⁴)hGD?(l-42)-OH (SEQ DD NO: 183);

Example 171: (Aib², A6c⁷)hGIP(l -42)-OH (SEQ ID NO: 184); Example 172: (Aib², A5c⁷, A6c¹⁴)hGB?(l-42)-OH (SEQ ID NO: 185);

Example 173: (Aib^{2 11}, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 186);

Example 174: (Aib², A5c^] ^hGIP(I -3O)-NH₂ (SEQ ID NO: 187);

Example 175: (Aib²' ¹³)hGIP(l -3O)-NH₂ (SEQ ID NO: 188);

Example 176: (Aib², A5c^u, A6c¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:189); Example 177: (Aib²' ¹³, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 190);

Example 178: (Aib², A5c^π, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 191);

Example 179: (Aib², A6c⁷' ¹⁴)hGIP(l-42)-OH (SEQ ID NO:192);

Example 180: (Aib², A6c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO: 193);

Example 181: (Aib², A5c' ^hGIP(I -42)-OH (SEQ ID NO:194); Example 182: (Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 195);

Example 183: (Aib², A6c⁷, Nle¹⁴)hGB?(l-42)-OH (SEQ ID NO: 196);

Example 184: (A5c^{2> 7}, A6c¹⁴)hGB?(l-42)-OH (SEQ ID NO: 197);

Example 185: (Aib²' ¹³, Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:198);

Example 186: (Aib², A5c⁷, Nle¹⁴)hGC?(l-42)-OH (SEQ ID NO: 199); Example 187: (Aib², A5c⁷' ¹⁴)hGIP(l-42)-OH (SEQ ID NO:200);

Example 188: (Aib^{2> l3})hGD?(l-42)-OH (SEQ ID NO:201);

Example 189: (Aib², A5c^u, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:202);

Example 190: (Pro³, Aib¹³, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:203);

Example 191 : (hPro³, Aib¹³, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:204); Example 192: (Dhp³, Aib¹³, Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:205);

Example 193: (hPro³, Aib¹³)hGD?(l-42)-OH (SEQ ID NO:206);

Example 194: (Tic³, Aib¹³)hGIP(l-42)-OH (SEQ ID NO:207);

Example 195: (4Hyp³, Aib¹³)hGIP(l-42)-OH (SEQ ID NO:208);

Example 196: (4Hyp\ Aib¹³, Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:209); Example 197: (Tic³, Aib¹³, Nle¹⁴)hGB?(l-42)-OH (SEQ ID NO:210);

Example 198: (3Hyp³, Aib¹³, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:211);

Example 199: (Tic³, A6c¹⁴)hGD?(l-42)-OH (SEQ ID NO:212); Example 200: (hPro³, A6c¹⁴)hGIP(l-42)-OH (SEQ ED NO:213);

Example 201 : [Aib², A6c⁷, Cys(Psu)⁴¹]hGIP(l-42)-OH (SEQ ID NO:214);

Example 202: (hPro³, A5c")hGIP(l-42)-OH (SEQ ID NO:215);

Example 203: (Pro³, Aib¹³)hGIP(l-42)-OH (SEQ ID NO:216); Example 204: (Pro³, A5c⁷' ¹⁴)hGEP(l-42)-OH (SEQ ID NO:217);

Example 205: (Pro³, A5c")hGEP(l-42)-OH (SEQ ID NO:218);

Example 206: [Aib², A6c⁷, Cys(Psu)⁴⁰]hGIP(l-42)-OH (SEQ ID NO:219);

Example 207: [Aib², A6c⁷, Cys(Psu)³⁹]hGD?(l-42)-OH (SEQ ID NO:220);

Example 208: [Aib², A6c⁷, Cys(Psu)³⁸]hGIP(l-42)-OH (SEQ ID NO:221); Example 209: [Aib², A6c⁷, Cys(Psu)³⁶]hGIP(l-42)-OH (SEQ ID NO:222);

Example 210: (Tic³, A5c^π)hGIP(l-42)-OH (SEQ ID NO:223);

Example 211 : (hPro³, A5c^u, A6c¹⁴)hGD?(l-42)-OH (SEQ ID NO:224);

Example 212: (4Hyp³, A6c¹⁴)hGB?(l-42)-OH (SEQ ID NO:225);

Example 213: [Aib², A6c⁷, Cys(Psu)³⁵]hGIP(l-42)-OH (SEQ ID NO:226); Example 214: [Aib², A6c⁷, Cys(Psu)³⁴]hGIP(l-42)-OH (SEQ ID NO:227);

Example 215: (4Hyp³, A5c^π)hGD?(l-42)-OH (SEQ ED NO:228);

Example 216: (4Hyp³, A5c^u, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:229);

Example 217: (Tic³, A5c^π, A6c¹⁴)hGEP(l-42)-OH (SEQ ID NO:230);

Example 218: [Aib², A6c⁷, Cys(Psu)³¹]hGEP(l-42)-OH (SEQ ID NO:231); Example 219: (Pro³, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO:232);

Example 220: (Pro³, A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:233);

Example 221 : (Aib², A6c⁷, Gln⁴³)hGD?(l-43)-OH (SEQ DD NO:234);

Example 222: [Aib², A5c⁷, Cys(Psu)³²]hGIP(l-42)-OH (SEQ ID NO:235);

Example 223: [Aib², A5c⁷, Cys(Psu)⁴³]hGD?(l-43)-OH (SEQ ID NO:236); Example 224: (Pro³, A5c", A6c¹⁴)hGEP(l-30)-NH₂ (SEQ ID NO:237);

Example 225: (Pro³, A6c⁷)hGIP(l -3O)-NH₂ (SEQ ED NO:238);

Example 226: (Pro³, A5c")hGIP(l -3O)-NH₂ (SEQ ED NO:239);

Example 227: [Aib², A6c⁷, Cys(Psu)³³]hGEP(l-42)-OH (SEQ ED NO:240);

Example 228: [Aib², A6c⁷, Cys(Psu)³⁷]hGEP(l-42)-OH (SEQ ED NO: 241); Example 229: (4Hppa', Aib¹³)hGEP(l-42)-OH (SEQ ED NO:242);

Example 230: (Pro³, A5c", A6c^M)hGEP(l-42)-OH (SEQ ED NO:243);

Example 231 : [Orn'(N-C(O)-(CH₂)_l2-CH3), A6c⁷]hGEP(l-42)-OH (SEQ ED NO:244);

Example 232: (D-AIa², A5cⁿ' ⁴⁰)hGEP(l-42)-OH;

Example 233: (D-AIa², A5c", His⁴³)hGEP(l-43)-OH; Example 234: (D-AIa², A5c"' ⁴¹)hGEP(l-42)-OH;

Example 235: (D-AIa², A6c"' ^l4'⁴¹)hGEP(l-42)-OH;

Example 236: (Aib²' ¹³, Pro³, Nle^M)hGEP(l -3O)-NH₂ (SEQ ED NO:245); Example 237: (Aib², Pro³, A6c⁷)hGIP( 1-3 O)-NH₂ (SEQ ID NO:246);

Example 238: (Aib², Pro³, A5c^π)hGIP(l-30)-NH₂ (SEQ ID NO:247);

Example 239: (Aib², Pro³, A5c", Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:248);

Example 240: (Aib², Pro³, A5c^u, A6c¹⁴)hGIP(l-30)-NH₂ (SEQ ID NO:249); Example 241 : (NMe-Tyr¹, Aib², A5c^π, Nle^I4)hGIP(l-42)-OH (SEQ ID NO:250);

Example 242: (GIy², A6c"' ^{14 41})hGIP(l-42)-OH (SEQ ID NO:251);

Example 243: (GIy², Aib¹³, A5c⁴⁰)hGIP(l-42)-OH (SEQ ID NO:252);

Example 244: (GIy², A5c^u'⁴¹)hGIP(l-42)-OH (SEQ ID NO:253);

Example 245: (GIy², A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO:254); Example 246: (3F-PlIe¹, Aib², A5c^{π> 14> 41})hGIP(l-42)-OH (SEQ ID NO:255);

Example 247: (3F-Phe\ Aib², A5c^{11 41}, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:256);

Example 248: (3F-Phe', Aib², A5c^{Ul 41}, His⁴³)hGIP(l-43)-OH (SEQ ID NO:257);

Example 249: (3F-Phe', Aib², A5c^u' ^{14 41}, His⁴³)hGIP(l-43)-OH (SEQ ID NO:258);

Example 250: deleted Example 251: (GIy², A5c^π, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:259);

Example 252: (D-AIa², A5c^u, NIe¹⁴, His⁴³)hGIP(l-43)-OH;

Example 253: (D-AIa², A5c^{π> 14}, His⁴³)hGIP(l-43)-OH;

Example 254: (D-AIa², A5c^{π> 14})hGIP(l -3O)-NH₂;

Example 255: (D-AIa², A5c^π, His³¹)hGIP(l-31)-NH₂; Example 256: (Aib², A5c^{11> 14}, His⁴³)hGIP(l-43)-OH (SEQ ID NO:260);

Example 257: (A5c^π)hGIP(l -3O)-NH₂ (SEQ ID NO:261);

Example 258: (A5c^π, His³ ^hGIP(I -31)-NH₂ (SEQ ID NO:262);

Example 259: (A5c^π' ¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:263);

Example 260: (A5c^π' ⁴¹, Cys³²)hGIP(l-42)-NH₂ (SEQ ID NO:264); Example 261 : (A5c^π'⁴¹, Cys³³)hGIP(l-42)-NH₂ (SEQ ID NO:265);

Example 262: (A5c^{11 41}, Cys⁴³)hGIP(l-43)-NH₂ (SEQ ID NO:266);

Example 263: [A5c^π, Orn³²(N-C(O)-(CH₂)₁₀-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:267);

Example 264: [A5c^π, Orn³³(N-C(O)-(CH₂)₁₀-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:268);

Example 265: [A5c^π, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH (SEQ ID NO:269); Example 266: [A5c", Cys³²(succinimide-N-(CH₂)_π-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:270);

Example 267: [A5c^π, Cys³³(succinimide-N-(CH₂)_π-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:271);

Example 268: [A5c^π, Cys⁴³(succinimide-N-(CH₂)_{ι r}CH₃)]hGIP(l-43)-OH (SEQ ID NO:272);

Example 269: [A5c^π, Lys⁴³(N-C(O)-(CH₂)₁₄-CH₃)]hGIP(l-43)-OH (SEQ ID NO:273);

Example 270: [A5c^π, Om³²(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:274); Example 271: [A5c^π, Orn³³(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:275);

Example 272: (3C1-Tyr', D-AIa², A5c", NIe¹⁴, His⁴³)hGIP(l-43)-OH;

Example 273: (3Cl-TyT¹, D-AIa², A5c"' ^M, His⁴³)hGIP(l-43)-OH; Example 274: (3Cl-TyT¹, Aib², A5c^u' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:276);

Example 275: (3Cl-TyT¹, Aib², A5c", NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:277);

Example 276: [3C1-Tyr\ Aib², A5cⁿ, NIe¹⁴, Orn⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH

(SEQ ID NO:278); Example 277: [3C1-Tyr', Aib², A5c", NIe¹⁴, Cys⁴³(succinimide-N-(CH₂)i,-CH₃)]hGIP(l-43)-OH (SEQ DD NO:279);

Example 278: [3Cl-TyT¹, D-AIa², A5c", NIe¹⁴, Orn⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

Example 279: [3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, Cys⁴³(succinimide-N-(CH₂)₁₁-CH₃)]hGIP(l-43)-OH;

Example 280: [3Cl-TyT¹, D-AIa², A5c"' ¹⁴, Orn⁴³(N-C(0)-(CH₂),o-CH₃)]hGIP(l-43)-OH; Example 281: [3Cl-TyT¹, D-AIa², A5c^{u> 14}, Cys⁴³(succinimide-N-(CH₂)π-CH₃)]hGIP(l-43)-OH;

Example 282: (3Br-TyT¹, Aib², A5c^π, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:280);

Example 283: (3Br-TyT¹, Aib², A5c^u' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:281);

Example 284: (3MeO-TyT¹, Aib², A5c^u, His⁴³)hGIP(l-43)-OH (SEQ ID NO:282);

Example 285: (3MeO-TyT¹, Aib², A5c^u' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ED NO:283); Example 286: (3MeO-TyT¹, Aib², A5c^π' ¹⁴'⁴¹, His⁴³)hGIP(l-43)-OH (SEQ ID NO:284);

Example 287: (4CF₃-PlIe¹, Aib², A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO:285);

Example 288: (7HO-Tic^!, Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:286);

Example 289: (4Me-Phe', Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:287);

Example 290: (4CN-PlIe¹, Aib², A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO:288); Example 291 : (hTyr¹, Aib², A5c^u, His⁴³)hGIP(l-43)-OH (SEQ ID NO:289);

Example 292: [3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

Example 293: [3Cl-TyT¹, D-AIa², A5c^{Ml 14}, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

Example 294: [3Cl-TyT¹, Aib², A5c^π, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH

(SEQ ED NO:290); Example 295: [3Cl-TyT¹, Aib², A5c^{Ul 14}, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH (SEQ ID NO:291);

Example 296: [3C1-Tyτ', Aib², A5c^π, NIe¹⁴, Cys⁴³]hGEP(l-43)-OH (SEQ ID NO:293);

Example 297: [3Cl-TyT¹, D-AIa², A5c", NIe¹⁴, Cys⁴³(succinimide)]hGIP(l-43)-OH;

Example 298: [3Cl-TyT¹, D-AIa², A5c"' ¹⁴, Cys⁴³(succinimide)]hGIP(l-43)-OH; and Example 299: [Aib², A5cⁿ, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGEP(2-43)-OH (SEQ ID NO:294).

It should be noted, however, that the present invention is not in any way limited to the above particularly preferred novel analogues of GEP. For instance, the present invention encompasses a pharmaceutical composition comprising (Pro³)GEP(l-42) (SEQ ED NO:9) disclosed in PCT Pub. No. WO 00/58360, and all other analogues of GEP specifically disclosed is the above-discussed PCT Pub. No. WO 00/58360, PCT Pub. No. WO 98/24464, and PCT Pub. No. WO 03/082898. In addition, the present invention encompasses the above illustrated GIP compounds which further comprise a covalently linked PEG moiety, in which said PEG moiety is covalently linked to the compound via a Cys(maleimide), hCys(maleimide), or Pen(maleimide) linker, to form Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG), wherein "succinimide-N-PEG" is either linear or branched as defined hereinbelow. Such PEG moiety has average molecular weight of from about 2,000 to about 80,000, and preferably such PEG moiety is selected from the group consisting of 5K PEG, 1OK PEG, 2OK PEG, 30K PEG, 4OK PEG, 50K PEG, and 6OK PEG, to form Cys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG), Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG), Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG), Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG), hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG), hCys(succinimide-N-30K PEG), hCys(succinimide-N-40K PEG), hCys(succinimide-N-50K PEG), hCys(succinimide-N-60K PEG), Pen(succinimide-N-5K PEG), Pen(succinimide-N-10K PEG), Pen(succinimide-N-20K PEG), Pen(succinimide-N-30K PEG), Pen(succinimide-N-40K PEG), Pen(succinimide-N-50K PEG), or Pen(succinimide-N-60K PEG).

PEGylation occurs at any one of amino acid residue positions 16, 30, and 31-43, and preferably at any one of amino acid residue positions 32, 33 and 43, whereby Cys(succinimide-N- PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of such amino acid residue positions. Further, the above formula (I) may be expanded to provide PEGylation sites at positions A⁴⁴-

A⁴⁷. The C-terminus of such PEGylated compounds of the present invention may be amidated, e.g., (Aib²' ") hGIP(l-42)-NH₂ (SEQ ID NO:292), or it may remain as free acid, e.g., (Aib²' ^π)hGIP(l-42)- OH (SEQ ID NO: 142).

(1) In one aspect, the present invention is directed to a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GDP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GD? peptide" or "GIP compound"), in which the aqueous solution of the GD? peptide forms a precipitate after subcutaneous or intramuscular administration to a subject. (2) The pharmaceutical composition according to paragraph 1, wherein said analogue of

GIP is any one of the above-listed Examples 1 to 295, hGIP(l-42)-NH₂ (SEQ DD NO:2), hGIP(l-30)-NH₂ (SEQ ID NO:3), hGIP(l-30)-OH (SEQ ID NO:4), hGIP(7-30)-NH₂ (SEQ ID NO:5), hGIP(7-30)-OH (SEQ ID NO:6), hGIP(6-30)-NH₂ (SEQ DD NO:7), hGIP(6-30)-OH (SEQ ID NO:8), (Pro³)hGIP(l-42)-OH (SEQ DD NO:9), (Pro³)hGD>(l- 42)-NH₂ (SEQ DD NO: 10), (Aib²)hGπ^>(l-42)-OH (SEQ DD NO: 11), (Aib²)hGD>(l-42)- NH₂ (SEQ ID NO: 12), (D-Ala²)hGIP(l-42)-OH, (D-Ala²)hGIP(l-42)-NH₂, (Aib²)hGIP(l -3O)-OH (SEQ ID NO: 13), (Aib²)hGIP(l -3O)-NH₂ (SEQ ID NO: 14), (D- Ala²)hGIP(l -3O)-NH₂, and (D-Ala²)hGIP(l -3O)-OH.

(3) The pharmaceutical composition according to paragraph 2, further comprising a divalent metal or divalent metal salt.

(4) The pharmaceutical composition according to paragraph 3, wherein said divalent metal is zinc, copper, calcium, or magnesium.

(5) The pharmaceutical composition according to paragraph 3, wherein said composition contains a divalent metal salt selected from the group consisting Of ZnCl₂, ZnAc₂, (C₆H₅Ov)₂Zn₃, CuCl₂, CuAc₂, (C₆H₅O₇)₂Cu₃, MgCl₂, MgAc₂, (C₆H₅O₇)₂Mg₃, CaCl₂,

CaAc₂, and (C₆H₅O_T)₂Ca₃.

(6) The pharmaceutical composition according to paragraph 4 or paragraph 5, further comprising water.

(7) The pharmaceutical composition according to any one of paragraphs 1-6, further comprising a non-aqueous medium.

(8) The pharmaceutical composition according to any one of paragraphs 1-7, wherein said GIP compound is present in an aqueous medium with pH between 2.0 and 10.5, preferably between 3 and 8.

(9) The pharmaceutical composition according to any one of paragraphs 1-8, wherein said GIP compound is present in a concentration of about from 0.001 to 500 mg/ml, preferably about from 0.1 to 400 mg/ml.

(10) The pharmaceutical composition according to any one of paragraphs 1-9, further comprising a preservative.

(11) The pharmaceutical composition according to paragraph 10, wherein said preservative is selected from the group consisting of m-cresol, phenol, benzyl alcohol, and methyl paraben.

(12) The pharmaceutical composition according to paragraph 11 , wherein said preservative is present in a concentration of about from 0.01 mg/ml to 100 mg/ml.

(13) The pharmaceutical composition according to any one of paragraphs 1-12, further comprising an isotonic agent.

(14) The pharmaceutical composition according to paragraph 13, wherein said isotonic agent is present in a concentration of about from 0.01 mg/ml to 100 mg/ml. (15) The pharmaceutical composition according to any one of paragraphs 1-14, wherein said zinc is present in a concentration of about from 0.0005 mg/ml to 50 mg/ml.

(16) The pharmaceutical composition according to any one of paragraphs 1-15, further comprising a stabilizer. (17) The pharmaceutical composition according to paragraph 16, wherein said stabilizer is selected from the group consisting of imidazole, arginine, and histidine.

(18) The pharmaceutical composition according to any one of paragraphs 1-17, further comprising a surfactant.

(19) The pharmaceutical composition according to any one of paragraphs 1-18, further comprising a chelating agent.

(20) The pharmaceutical composition according to any one of paragraphs 1-19, further comprising a buffer.

(21) The pharmaceutical composition according to paragraph 20, wherein said buffer is selected from the group consisting of Tris, ammonium acetate, sodium acetate, glycine, aspartic acid, and Bis-Tris.

(22) The pharmaceutical composition according to any one of paragraphs 1-21, further comprising a basic polypeptide.

(23) The pharmaceutical composition according to paragraph 22, wherein said basic polypeptide is selected from the group consisting of polylysine, polyarginine, polyornithine, protamine, putrescine, spermine, spermidine, and histone.

(24) The pharmaceutical composition according to any one of paragraphs 1-23, further comprising alcohol, monosaccharide, or disaccharide.

(25) The pharmaceutical composition according to paragraph 24, wherein said alcohol, monosaccharide, or disaccharide is selected from the group consisting of methanol, ethanol, propanol, glycerol, trehalose, mannitol, glucose, erythrose, ribose, galactose, fructose, maltose, sucrose, and lactose.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the full time course plot of the pharmacokinetic profile (median values) obtained after a single subcutaneous administration to Sprague Dawley rats dosed at 0.9 mg/rat (6 μl of 15% solution) with the molar ratio of the peptide of Example 2 to ZnCl₂ of 0.5:1.

FIG. 2 shows the estimated percentage of Example 2 remaining at the injection site of Sprague Dawley rats after a single subcutaneous administration of the test formulation shown in FIG. 1. FIG. 3 shows the full time course plot of the pharmacokinetic profile (median values) obtained after a single subcutaneous administration to Sprague Dawley rats dosed at 0.9 mg/rat (6 μl of 15% solution) with the molar ratio of the peptide of Example 3 to ZnCl₂ of 0.5: 1.

FIG. 4 shows the estimated percentage of Example 3 remaining at the injection site of Sprague Dawley rats after a single subcutaneous administration of the test formulation shown in FIG. 3.

FIG. 5 shows the in vivo effects of the compounds of Examples 1-7 and the native GIP on insulin release of Sprague Dawley rats.

DETAILED DESCRIPTION OF THE INVENTION The application employs the following commonly understood abbreviations:

Abu: cc-aminobutyric acid

Ace : 1 -amino- 1 -cyclo(C₃-C₉)alkyl carboxylic acid

A3c: 1 -amino- 1-cyclopropanecarboxylic acid

A4c: 1 -amino- 1 -cyclobutanecarboxylic acid A5c : 1 -amino- 1 -cyclopentanecarboxylic acid

A6c : 1 -amino- 1 -cyclohexanecarboxylic acid

Act: 4-amino-4-carboxytetrahydropyran

Ado: 12-aminododecanoic acid

Aib: α-aminoisobutyric acid Aic: 2-aminoindan-2 -carboxylic acid

Ala or A: alanine β-Ala: beta-alanine

Amp: 4-amino-phenylalanine;

Ape: 4-amino-4-carboxypiperidine: Arg or R: arginine hArg: homoarginine

Asn or N: asparagine

Asp or D: aspartic acid

Aun: 11-aminoundecanoic acid Ava: 5-aminovaleric acid

Cha: β-cyclohexylalanine

Che: cyclohexyl carboxylic acid

Cpa: 4-Cl-phenylalanine

Cys or C: cysteine D-AIa: D-alanine

Dhp: 3,4-dehydroproline Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid

Gaba: γ-aminobutyric acid

GIn or Q: glutamine

GIu or E: glutamic acid

GIy or G: glycine

His or H: histidine

4Hppa: 3-(4-hydroxyphenyl)propionic acid

Hsu: N-hexylsuccinimide

3Hyp: 3 -hydroxyproline

4Hyp: 4-hydroxyproline hPro: homoproline lie or I: isoleucine

4Ktp: 4-ketoproline

Leu or L: leucine

Ly s or K: lysine

Met or M: methionine

NIe: norleucine

NMe-Tyr: N-methyl-tyrosine

INaI: β-( 1 -naphthyl)alanine

2NaI: β-(2-naphthyl)alanine

NIe: norleucine

Nva: norvaline

Orn: ornithine

2PaI: β-(2-pyridinyl)alanine

3PaI: β-(3 -pyridinyl)alanine

4PaI: β-(4-pyridinyl)alanine

Pen: penicillamine

Phe or F: phenylalanine

(3,4,5F)Phe: 3,4,5-trifluorophenylalanine

(2,3,4,5,6)Phe: 2,3,4,5,6-pentafluorophenylalanine

3,4,5F-Phe: 3,4,5-trifluoro-phenylalanine

3,4F-Phe: 3 ,4-difluoro-phenylalanine

3,5F-Phe: 3,5-difluoro-phenylalanine

3Br-Phe: 3 -bromo-phenylalanine

3C1-Phe: 3-chloro-phenylalanine

3F-Phe: 3 -fluoro-phenylalanine

3OH-Phe: 3 -hydroxy-phenylalanine 4CN-Phe: 4-cyano-phenylalanine

4F-Phe: 4-fluoro-phenylalanine

4NH₂CH₂-Phe: 4-aminomethyl-phenylalanine

4NH₂-Phe: 4-amino-phenylalanine

Pro or P: proline

Psu: N-propylsuccinimide

Ser or S: serine

Taz: β-(4-thiazolyl)alanine

3Thi: β-(3 -thienyl)alanine

Thr or T: threonine

Thz: thioproline

Tic: tetrahydroisoquinoline-3 -carboxylic acid

Tie: tert-leucine

Tip or W: tryptophan

Tyr or Y: tyrosine

Tyr(Ac): tyrosine(acetyl)

Tyr(Me): tyrosine(O-methyl) β-Tyr: β-tyrosine αMe-Tyr: α-methyl-tyrosine

2,6Me-Tyr: 2,6-dimethyl-tyrosine

2F-Tyr: 2-fluoro-tyrosine

3,5Br-Tyr: 3 ,5 -dibromo-ryrosine

3,51-Tyr: 3 , 5 -diiodo-tyrosine

3Br-Tyr: 3 -bromo-tyrosine

3C1-Tyr: 3-chloro-tyrosine

3F-Tyr: 3-fluoro-tyrosine

3I-Tyr: 3-iodo-tyrosine

3MeO-Tyr: 3 -O-methyl -tyrosine

3NH₂-Tyr: 3 -amino-tyrosine

3NO₂-Tyr: 3-nitro-tyrosine

3(OH-CH₂)Tyr: 3 -methylhydroxy-tyrosine

3OH-Tyr: 3 -hydroxy-tyrosine

VaI or V: valine other abbreviations used herein are defined as follows:

Acn: acetonitrile

Boc: tert-butyloxycarbonyl BSA: bovine serum albumin

DIPEA: diisopropylethyl amine

DMF: dimethylformamide

DTT: dithiothrietol Fmoc: 9-Fluorenylmethyloxycarbonyl

HBTU: 2-( 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate

HOBT: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

IBMX: isobutylmethylxanthine LC-MS: liquid chromatography-mass spectrometry

LOQ : limit of quantification

MRM: multiple reaction monitoring

NMP: N-methylpyrrolidone

PBS: phosphate buffered saline 5K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 5,000

1OK PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 10,000

2OK PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 20,000

3OK PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 30,000

4OK PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 40,000 50K PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 50,000

6OK PEG: polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 60,000 tBu: tert-buty\

TIS: triisopropylsilane Trt: trityl

TFA: trifluoro acetic acid

Z: benzyloxycarbonyl

"4CF₃-Phe", i.e., 4-trifluoromethyl -phenylalanine, has the structure of:

"7HO-Tic", i.e., 7-hydroxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, has the structure

"Tyr ' -Ψ-(CH₂-NH)" has the structure of:

The Greek letter psi "Ψ" is used herein to indicate that a peptide bond has been replaced by a pseudopeptide bond. In an amino acid sequence name, the format of the Ψ term is A'-Ψ-(X-X')A² wherein A¹ is the amino acyl radical whose carbonyl group has been modified to X and A² is the amino acyl radical whose α-amino group has been modified to X'. X and X¹ are shown as strings of element symbols separated by a bond, e.g. , Tyr-Ψ-(CH₂-NH)Gly.

"Cys(succinimide-N-alkyl)" has the structure of:

"Cys(Hsu)" has the structure of:

-

"Cys(Psu)" has the structure of:

"Orn(N-C(O)-(CH₂)₁₂-CH₃)" has the structure of:

"Cys(succinimide-N-(CH₂)_x-C(O)-NH-(CH₂)_y-CH₃)" has the structure of:

wherein, x = 1-30, and y = 1-30. "hCys(succinimide-N-(CH₂)_x-C(O)-NH-(CH₂)_y-CH₃)" has the structure of:

wherein, x = 1-30, and y = 1-30.

"Pen(succinimide-N-(CH₂)_x-C(O)-NH-(CH₂)_y-CH₃)" has the structure of:

wherein, x = 1-30, and y = 1-30.

"Cys(succinimide-N-(CH₂)_s-NH-C(O)-(CH₂)_t-CH₃)" has the structure of:

wherein, s = 1-30, and t = 1-30.

"hCys(succinimide-N-(CH₂)_s-NH-C(O)-(CH₂)_rCH₃)" has the structure of:

wherein s = 1-30, and t = 1-30. "Pen(succinimide-N-(CH₂)_s-NH-C(O)-(CH₂)_t-CH₃)" has the structure of:

wherein s = 1-30, and t = 1-30.

"Cys(succinimide-N-PEG)" has the structure of:

"hCys(succinimide-N-PEG)" has the structure of:

"PenCsuccinimide-N-PEG)" has the structure of:

"Cys(succinimide-N-(CH₂)₂-C(O)NH-(CH₂)₃-PEG)" has the structure of:

"Cys(succinimide-N-(CH₂)₂-C(O)NH-(CH₂)₃-O-CH₂-CH(PEG)-CH₂-PEG)" has the structure of:

With the exception of the N-terminal amino acid, all abbreviations (e.g., Ala) of amino acids in this disclosure stand for the structure of -NH-C(R)(R')-CO-, wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R = CH₃ and R' = H for Ala), or R and R' may be joined to form a ring system. For the N-terminal amino acid, the abbreviation stands for the structure of (R²R³)N-C(R)(R')-CO-, wherein R² and R³ are as defined in the above formula (I).

The term "(Ci-C₃₀)hydrocarbon moiety" encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are C₂-C₃₀.

A peptide of this invention is also denoted herein by another format, e.g., (A5c²)hGEP(l-42)- OH (SEQ ID NO:295), with the substituted amino acids from the natural sequence placed between the brackets (e.g., A5c² for Ala² in hGIP). The numbers between the parentheses refer to the number of amino acids present in the peptide (e.g., hGIP(l-42)-OH (SEQ ED NO:1) is amino acids 1 through 42 of the peptide sequence for hGIP). The designation "NH₂" in hGIP(l -3O)-NH₂ (SEQ ED NO:3) indicates that the C-terminus of the peptide is amidated; hGIP(l-42) (SEQ ID NO:1) or hGIP(l-42)- OH (SEQ ID NO:1) means that the C-terminus is the free acid.

Human GIP ("hGIP") has the amino acid sequence of:

Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val- 1 5 10 15 20

Asn-Tφ-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Tφ-Lys-His-Asn-Ile-Thr-Gln. (SEQ ID NO: 1) 25 30 35 40

"Acyl" refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl. "Alkyl" refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight- chain or contain one or more branches or cyclic groups.

"Substituted alkyl" refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH₂, -NHCH₃, -NO₂, -Ci_-20 alkyl substituted with halogens, -CF₃, -OCH₃, -OCF₃, and -(CH₂)₀-₂₀-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of-(CH₂)₀.₂o-COOH results in the production of an alkyl acid. Examples of alkyl acids containing, or consisting of, -(CH₂)_0-20-COOH include 2-norbomane acetic acid, tert-butyric acid and 3-cyclopentyl propionic acid. "Heteroalkyl" refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group are replaced with one or more of the following groups: amino, amido, -O-, -S- or carbonyl. In different embodiments 1 or 2 heteroatoms are present.

"Substituted heteroalkyl" refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, -OH, -CN, -SH, -NH₂, -NHCH₃, -NO₂, -Ci_-20 alkyl substituted with halogens, -CF₃, -OCH₃, -OCF₃, and -(CH₂)_0-20-COOH. In different embodiments 1, 2, 3 or 4 substituents are present.

"Alkenyl" refers to a hydrocarbon group made up of two or more carbons wherein one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.

"Substituted alkenyl" refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen, -OH, -CN, -SH, -NH₂, -NHCH₃, -NO₂, -C_1-20 alkyl substituted with halogens, -CF₃, -OCH₃, -OCF₃, and -(CH₂V₂₀-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. "Aryl" refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to three conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5 or 6 membered ring. Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen. Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and 9-anthracene. Aryl substituents are selected from the group consisting Of-C_1-20 alkyl, -C_1-2O alkoxy, halogen, -OH, -CN, -SH, -NH₂, -NO₂, -C_1-20 alkyl substituted with halogens, -CF₃, -OCF₃, and - (CH₂)o_-20-COOH. In different embodiments the aryl contains O, 1,2, 3, or 4 substituents.

"Alkylaryl" refers to an "alkyl" joined to an "aryl". Synthesis

The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J. M., et al, 1984, Solid Phase Synthesis, Pierce Chemical Co., 2d ed. The following examples describe synthetic methods for making a peptide of this invention, which methods are well- known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration and are not meant to limit the scope of the present invention in any manner.

Example 15: rA6c⁷. CvsfPsuV²lhGIPq-42VOH

Solid-phase peptide synthesis was used to assemble the peptide using microwave-assisted Fmoc Chemistry on a Liberty Peptide Synthesizer (CEM; Matthews, NC, USA) at the 0.1 mmole scale. Pre-loaded Fmoc-Cys(Trt)-Wang resin (0.59 mmole/g; Novabiochem, San Diego, CA, USA) was used to generate the C-terminal acid peptide. The resin (0.17 g) was placed in a 50 ml conical tube along with 15 ml of dimethylformamide (DMF) and loaded onto a resin position on the synthesizer. The resin was then quantitatively transferred to the reaction vessel via the automated process. The standard Liberty synthesis protocol for 0.1 mmole scale synthesis was used. This protocol involves deprotecting the N-terminal Fmoc moiety via an initial treatment with 7 ml of 20% piperidine, containing 0.1M N-hydroxybenzotriazole (HOBT), in DMF. The initial deprotection step was for 30 seconds with microwave power (45 watts, maximum temperature of 75 ⁰C), and nitrogen bubbling (3 seconds on / 7 seconds off). The reaction vessel was then drained and a second piperidine treatment, identical to the first treatment, except that it was for a 3 -minute duration. The resin was then drained and thoroughly washed with DMF several times. The protected amino acid, Fmoc- Thr(tBu)-OH, prepared as 0.2M stock solution in DMF, was then added (2.5 ml, 5 eq.), followed by 1.0 ml of 0.45M (4.5 eq.) HBTU [2-(lH-benzo-triazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosaphate] in DMF. This was followed by the addition of 0.5 ml of 2M (10 eq.) DEPEA (diisopropylethyl amine) in NMP (N-methylpyrrollidinone). The coupling step was performed for 5 minutes using 20 watts of microwave power, a max temperature of 75 ⁰C, and the same rate of nitrogen bubbling.

Following the initial coupling step the reaction vessel was drained to waste and the coupling step repeated. Cycle 2 was then initiated similar to cycle 1. All amino acids were introduced similarly and a double-coupling strategy was employed throughout the entire sequence. Cycles 1-3, 19-20, 25-26, and 30-39 contained a capping procedure immediately following the coupling step. Capping was performed by adding 7 ml of 0.5M acetic anhydride, containing 0.015M HOBT in NMP, along with 2 ml of the 2M DIPEA solution using a multi-step microwave protocol: 50 watts of power for 30 seconds (65 ⁰C max temperature), followed by 30 seconds of microwave power off, followed by a second round of 30 seconds of microwave power on (50 watts), and then again 30 seconds of no microwave power. The resin was then drained and thoroughly washed with DMF. The following amino acids (Advanced Chemtech, Louisville, KY, USA) were used: Cycle 1 : Fmoc-Thr(OtBu)-OH; Cycle 2: Fmoc-Ile-OH; Cycle 3: Fmoc-Asn(Trt)-OH; Cycle 4: Fmoc-His(Trt)-OH; Cycle 5: Fmoc- Lys(Boc)-OH; Cycle 6: Fmoc-Trp(Boc)-OH; Cycle 7: Fmoc-Asp(OtBu)-OH; Cycle 8: Fmoc- Asn(Trt)-OH; Cycle 9: Fmoc-Lys(Boc)-OH; Cycle 10: Fmoc-Lys(Boc)-OH; Cycle 11 : Fmoc-Gly-OH; Cycle 12: Fmoc-Lys(Boc)-OH; Cycle 13: Fmoc-Gln(Trt)-OH; Cycle 14: Fmoc-Ala-OH; Cycle 15: Fmoc-Leu-OH; Cycle 16: Fmoc-Leu-OH; Cycle 17: Fmoc-Trp(Boc)-OH; Cycle 18: Fmoc-Asn(Trt)- OH; Cycle 19: Fmoc-Val-OH; Cycle 20: Fmoc-Phe-OH; Cycle 21 : Fmoc-Asp(OtBu)-OH; Cycle 22: Fmoc-Gln(Trt)-OH; Cycle 23: Fmoc-Gln(Trt)-OH; Cycle 24: Fmoc-His(Trt)-OH; Cycle 25: Fmoc- He-OH; Cycle 26: Fmoc-Lys(Boc)-OH; Cycle 27: Fmoc-Asp(OtBu)-OH; Cycle 28: Fmoc-Met-OH; Cycle 29: Fmoc-Ala-OH; Cycle 30: Fmoc-He-OH; Cycle 31 : Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; Cycle 32: Fmoc-Asp(OtBu)-OH; Cycle 33: Fmoc-Ser(tBu)-OH; Cycle 34: Fmoc-A6c-OH. Cycle 35: Fmoc-Phe-OH; Cycle 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; Cycle 37: Fmoc-Glu(OtBu)-OH; Cycle 38: Fmoc-Ala-OH; and Cycle 39: Fmoc-Tyr(tBu)-OH. The coupling protocol for Fmoc-His(Trt)-OH was a slightly modified version of the standard protocol. The microwave power was off for the first 2 minutes, followed by 4 minutes with microwave power on (20 watts; max temperature of 50 ⁰C). Once the peptide backbone was complete, standard piperidine treatment was used to remove the N- terminal Fmoc group. The resin was then thoroughly washed with DMF and then transferred back to the 50 ml conical tube using DMF as the transfer solvent. The resin was deprotected and cleaved from the resin via treatment with 5 ml of the following reagent: 5% TIS, 2% water, 5% (w/v) dithiothrieitol (DTT), 88% TFA, and allowed to mix for 3.5 hours. The filtrate was collected into 45 ml of cold anhydrous ethyl ether. The precipitate was pelleted for 10 minutes at 3500 RPM in a refrigerated centrifuge. The ether was decanted, and the peptide re-suspended in fresh ether. The ether workup was performed a total of 2 times. Following the last ether wash the peptide was allowed to air dry to remove residual ether. The peptide pellet was resuspended in 8 ml of acetonitrile (Acn) followed by 8 ml of de-ionized water, and allowed to fully dissolve. The peptide solution was then analyzed by mass spectrometry. Mass analysis employing electrospray ionization identified a main product containing a mass of 4970.7 da; corresponding to the linear product. The crude product (approximately 500 mg) was analysed by HPLC, employing a 250 x 4.6mm Cl 8 column (Phenomenex; Torrance, CA, USA) using a gradient of 2-80% acetonitrile (0.1% TFA) over 30 minutes. The crude peptide was then derivatized with N-propylmaleimide (Pma) to generate the propylsuccinimide (Psu) derivative on the Cysteine side chain. The crude linear peptide was brought up in water, adjusted to pH 6.5 with ammonium carbonate, at 5 mg/ml. Five equivalents of Pma was added with constant stirring for 30 seconds. Excess Pma was quenched using 5 eq. of dithiothreitol (DTT). The derivatized peptide solution was then analyzed by mass spectrometry. Mass analysis identified a main product containing a mass of 5109.7 da; corresponding to the desired Psu derivatized product. The product was then purified via preparative HPLC using a similar gradient as before. The purified product was analyzed by HPLC for purity (96.60%) and mass spectrometry (5108.9 Daltons) and subsequently lyophilized. Following lyophillization, 10.3 mg of purified product was obtained representing a 2% yield. The PEGylated GIP compounds disclosed herein can be synthesized substantially according to the procedure described for the synthesis of the compound of Example 15, by using PEG- maleimide as the starting material instead of N-propylmaleimide used in Example 15.

Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed in the foregoing examples. Physical data for the compounds exemplified herein are given in Table 1.

TABLE l

Functional Assays A. In Vitro hGEP Receptor Binding Assay

Membranes for in vitro receptor binding assays were prepared by homogenizing the CHO-Kl clonal cells expressing the human recombinant GIP receptor, with a Brinkman Polytron (setting 6, 15 sec), in ice-cold 50 mM Tris-HCl and then subjected to two centrifugations at 39,000 g for 10 minutes with a resuspension in fresh buffer in between. For the assay, aliquots of the washed membrane preparations were incubated (100 minutes at 25 ⁰C with 0.05 nM [¹²⁵I]GIP (approximately 2200 Ci/mmol) in 5OmM Tris-HCl, O.lmg/ml bacitracin, and 0.1% BSA. The final assay volume was 0.5 ml. The incubations were terminated by rapid filtration through GF/C filters (pre-soaked in 0.5% polyethylenimine) using a Brandel filtration manifold. Each tube and filter were then washed three times with 5-ml aliquots of ice-cold buffer. Specific binding was defined as the total radioligand bound minus that bound in the presence of 1000 nM GIP. In vitro hGIP receptor binding data for the compounds exemplified herein are given in Table 2.

B. Human and Rat Plasma Half-Life Assay

GlP peptide (50 μL 1 mg/mL) was added to 450 μL plasma (human or rat), vertexed briefly and incubated at 37 ⁰C. 50 μL was removed at various times, like at 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72 hours, mixed with 5 μL formic acid and 150 μL acetonitrile in a microcentrifuge tube, vertexed, and centrifuged for 10 minutes at 1OK rpm. The supernatant was transferred to an injection vial and analyzed by LC-MS. The LC-MS system consisted of an API4000 mass spectrometer with an ESI probe. Positive ion mode and full scan detection were used. HPLC separation was carried out on a Luna 3μ C8 (2), 2 x 30 mm column with a gradient from 90% A to 90% B in 10 minutes at a flow rate of 0.3 ml/min. Buffer A was 1% formic acid in water and buffer B was 1% formic acid acetonitrile. Human and rat plasma half-life data for the compounds exemplified herein are given in Table 2.

TABLE 2

In comparison to the data listed in Table 2, the in vitro hGEP receptor binding data, and human and rat plasma half-life data for [Pro³]hGIP(l-42)-OH, a compound disclosed in PCT Pub. No. WO 00/58360, were measured under the same experimental conditions as described hereinabove to be 170.8 nM, and 10.8 hours and 0.8 hours, respectively.

C. Determination of cyclic AMP stimulation

1 x 105 CHO-Kl cells expressing the human recombinant GIP receptor or RIN-5F insulinoma cells were seeded overnight into 24-well cell culture plates (Corning Incorporate, Corning, NY, USA). For the assay, the cells were preincubated in 500 μl of Hanks balanced salt solution (Sigma, St. Louis, MO, USA) with 0.55 mM IBMX (Sigma, St. Louis, MO, USA) adjusted to pH 7.3 for 10 minutes. GIP or its analogs was then added at a concentration of 100 nM. Following a 30-minute incubation at 37 ⁰C, the plates were placed on ice and 500 μl of ice-cold absolute ethanol was added to stop the reaction. The contents of the wells were collected, spun at 2,700 g for 20 minutes at 4 ⁰C to remove cellular debris. The cAMP levels in the supernatants were determined by radioimmunoassay (New England Nuclear, Boston, MA, USA).

D. Determination of in vivo Insulin Secretion in Normal Rats

Male Sprague Dawley rats with a body weight of approximately 275-300 g were used as experimental subjects. The day prior to the treatment, right atrial cannulae were implanted via the jugular vein under chlorohydrate. Each cannula was filled with 100 u/ml heparin saline and tied. The rats were fasted for approximately 18 hours prior to dosing with the compound or the vehicle (saline/0.25% BSA). The day of the experiment, aliquots of compound were thawed, brought to room temperature and vortexed thoroughly. A careful check was made for any sign of compound coming out of solution. 10 minutes prior to compound/glucose injection, a 500-μl blood sample was withdrawn and replaced with an equal volume of heparinized saline (10 u/ml). At time 0, a 500-μl blood sample was withdrawn through the cannula. Next, either the vehicle or the appropriate dose of the compound was injected into the cannula and pushed in with the glucose (1 g/kg) or vehicle solution. Finally, 500 μl of volume of heparinized saline (10 u/ml) was used to push in the remaining glucose through the cannula. Additional 500 μl blood samples were withdrawn at 2.5, 5, 10, and 20- minute post-glucose dosing; each immediately followed by a bolus, iv injection of 500 μl heparinized saline (10 u/ml) through the cannula. The plasma was collected from the blood samples by centrifugation, and stored at -20 ⁰C until assay for insulin content.

FIG. 5 shows the in vivo effects of the compounds of Examples 1-7 and the native GIP on insulin release of Sprague Dawley rats. Numerical values of the total insulin secretion shown in FIG. 5 are summarized in Table 3. In addition, the in vivo effects of the compounds of Examples 20, 41, 55, 233, 234, 251 , and 252 were determined in separate tests under the identical experimental conditions as described above, and numerical values of the total insulin secretion for the compounds of Examples 20, 41, 55, 233, 234, 251, and 252 are summarized in Table 4.

TABLE 3

AUC

Vehicle/Vehicle 33.86

Vehicle/Glucose 90.77

GIP 114.87

Example 1 304.92

Example 2 286.02

Example 3 269.83

Example 4 265.11

Example 5 196.17

Example 6 180.31

Example 7 176.90

TABLE 4

AUC

Vehicle/Vehicle 20.54

Vehicle/Glucose 4.11

Example 20 149.39

Example 41 189.54

E. Determination of Solubility

Four aliquots of a GIP peptide were weighed (0.4 mg each) and put into four glass vials. 200 μl of PBS at pH 7, 200 μl of PBS at pH 7 with 100 μg/ml ZnCl₂, 200 μl of PBS at pH 4, and 200 μl of PBS at pH 4 with 100 μg/ml ZnCl₂ were added respectively into the four glass vials containing the GIP peptide. The glass vials were shaken thoroughly and monitored for the solubility of the peptide. If the solution was clear, the solubility was recorded as >2 mg/ml. If the solution is cloudy, then the concentration of the peptide in the solution is determined by HPLC. The cloudy solution was centrifuged and the supernatant was injected for HPLC analysis. A Luna 3μ C18(2) 4.6 x 100 mm column was run from 95% A (0.1% TFA water) to 80% B (0.1% TFA acetonitrile) in 30 minutes at a flow rate of 1 ml/min at room temperature. UV detector was set at 220 nm. A standard calibration curve was generated to calculate the concentration of the peptide in the solution, which was reported as the solubility of the peptide in the corresponding buffer. The results are listed in Table 5.

TABLE 5

In comparison to the data listed in Table 4, the solubility at pH 7 without zinc and with zinc and the solubility at pH 4 without zinc and with zinc of (Pro³)hGIP(l-42)-OH, a compound disclosed in PCT Pub. No. WO 00/58360, were measured under the same experimental conditions as described hereinabove to be >2, 0.92, >2 and >2, respectively. F. Pharmacokinetic Studies of Formulations of Examples 2 and 3

Peptide Samples Formulations of Examples 2 and 3 were prepared by using the following procedures.

(1) The molar ratio of the peptide of Example 2 to ZnCl₂ is 0.5: 1. The peptide concentration is 15% in water (w/v) with pH of about 3, which can be adjusted by using NaOH or HCl aqueous solutions.

(2) The molar ratio of the peptide of Example 3 to ZnCl₂ is 0.5: 1. The peptide concentration is 15% in water (w/v) with pH of about 3 , which can be adjusted by using NaOH or HCl aqueous solutions.

Dosing and Blood Sample Collection

Sprague Dawley rats were dosed at 0.9 mg/rat (6 μl of 15% solution) subcutaneously with these peptide formulations. Blood samples were collected at 5, 10, 15, 30 minutes, 1, 2, 4, 8 hours, and 1, 2, 3, 4, 7 days. Plasma was collected from the blood by centrifugation and stored at -8O⁰C. The tissue at the injection site was also collected, homogenized in 5x methanol, and stored at -8O⁰C. Two samples were collected for each time point.

Sample Preparation

Plasma (200 μl) was acidified with 10 μl of formic acid and precipitated with 600 μl of acetonitrile. The supernatant was collected by centrifugation and concentrated to dryness under vacuum. The residues were dissolved in 100 μl of 30% acetonitrile in water and centrifuged. 50 μl of the supernatant was injected for LC-MS/MS analysis. Tissue methanol extract (50 μl) was directly injected for LC-MS/MS analysis.

LC-MS/MS Analysis

LC-MS/MS analysis was done with an API4000 mass spectrometer system equipped with a Turbo Ionspray probe. The MRM mode of molecular ion detection was used with the ion pair of 835.5 and 136.1 for Example 2, and the ion pair of 858.5 and 136.1 for Example 3. HPLC separation was performed with a Symmetry C4 2.1 x 50 mm 3.5 μ column run from 30% B to 95% B in 10 minutes at a flow rate of 0.30 ml/minute. Buffer A is 1% formic acid in water and buffer B is 1% formic acid in acetonitrile. LOQ was 2.0 ng/ml for Example 2, and 1.0 ng/mL for Example 3. Results and Summary

The plasma concentrations of the peptide were calculated with its standard calibration curve. 0.18 mg/ml of Examples 2 and 3 (0.9 mg/rat in 5 ml methanol extract) was used as the 100% to calculate the percentages left at the injection sites. The results are listed in Table 6.

TABLE 6

Full time course plot of the pharmacokinetic profile of the Example 2 formulation is shown in

FIG. 1.

The tissue accumulation profile of Example 2 at the injection site is shown in FIG. 2.

Full time course plot of the pharmacokinetic profile of the Example 3 formulation is shown in

FIG. 3.

The tissue accumulation profile of Example 3 at the injection site is shown in FIG. 4. Some pharmacokinetic profiles of Examples 2 and 3 are shown in Table 7.

TABLE 7

The results indicate that the peptides of GIP disclosed in the present application, particularly in combination with a divalent metal salt, provide for acceptable sustained release formulations. The data also indicate that, after the subcutaneous injection, the GIP compound precipitated at the injection site and formed a depot. The GIP compound was then slowly released into the body fluid and the bloodstream.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents and other references mentioned herein are hereby incorporated by reference, each in its entirety.

Additional embodiments of the present invention will be apparent from the foregoing disclosure and are intended to be encompassed by the invention as described fully herein and defined in the appended claims.

Claims

CLAIMS What is claimed is: 1. A pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GEP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (collectively referred to as "GEP compound"), in which the clear aqueous solution of the GEP compound forms a precipitate after subcutaneous or intramuscular administration to a subject.

2. The pharmaceutical composition according to claim 1, wherein said GEP compound is:

(A5c^{11 41})hGEP(l-42)-OH (SEQ ED NO: 15);

(A5c^{n> 40})hGEP(l-42)-OH (SEQ ED NO: 16);

(A5c^π, His⁴³)hGEP(l-43)-OH (SEQ EO NO: 17);

(A5cⁿ, Asn⁴³)hGEP(l-43)-OH (SEQ ED NO: 18); (Aib¹³, Asp⁴³)hGEP(l-43)-NH₂ (SEQ ED NO: 19);

(Aib¹³, NIe¹⁴, A5c⁴⁰)hGEP(l-42)-OH (SEQ ED NO:20);

(Aib¹³, A5c⁴⁰)hGEP(l-42)-OH (SEQ ED NO:21);

(A5c", Ala⁴³)hGEP(l-43)-OH (SEQ ED NO:22);

(Aib¹³, NIe¹⁴, Phe⁴³)hGEP(l-43)-OH (SEQ ED NO:23); (A5cⁿ, Thr⁴³)hGEP(l-43)-OH (SEQ ED NO:24);

(AOc¹¹' ¹⁴'⁴¹)hGEP(l-42)-OH (SEQ ED NO:25);

(Aib¹³, Trp⁴³)hGEP(l-43)-OH (SEQ ED NO:26);

(A5c^u, Ado⁴³)hGEP(l-43)-OH (SEQ ED NO:27);

(A6c^{u> 14 40})hGEP(l-42)-OH (SEQ ED NO:28); [A6c⁷, Cys(Psu)⁴²]hGEP(l-42)-OH (SEQ ED NO:29);

(A6c^{7 41})hGEP(l-42)-OH (SEQ ED NO:30);

(A6c⁷- ⁴¹, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:31);

[A6c⁷, Orn³⁵(N-C(O)-(CH₂)₁₂-CH₃)]hGIP(l-42)-OH (SEQ ED NO:32);

[A6c⁷, Orn³¹(N-C(O)-(CH₂)₁₂-CH₃)]hGEP(l-42)-OH (SEQ ED NO:33); (A5c^{Ml 14}, His⁴³)hGEP(l-43)-OH (SEQ ED NO:34);

(A5cⁿ, NIe¹⁴, His⁴³)hGEP(l-43)-OH (SEQ ED NO:35);

[A5cⁿ, Orn³²(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGEP(l-43)-OH (SEQ ED NO:36);

[A5c", Orn³³(N-C(O)-(CH₂)₁₄-CH₃)_> His⁴³]hGEP(l-43)-OH (SEQ ED NO:37);

[A5c", Orn⁴³(N-C(O)-(CH₂)₁₄-CH₃)]hGEP(l-43)-OH (SEQ ED NO:38); [A5c", Cys³²(succinimide-N-(CH₂)₁₅-CH₃), His⁴³]hGEP(l-43)-OH (SEQ ED NO:39);

[A5c^π, Cys³³(succinimide-N-(CH₂)₁₅-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ED NO:40);

[A5c", Cys⁴³(succinimide-N-(CH₂)₁₅-CH₃)]hGEP(l-43)-OH (SEQ ED NO:41);

(4HpPa¹, Aib², A5c⁷, Nle¹⁴)hGEP(l -3O)-NH₂ (SEQ ED NO:42); (4HpPa¹, Aib²' ^u, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ DD NO:43);

(4HpPa¹, Aib², A5c>GIP(l -3O)-NH₂ (SEQ ED NO:44);

(4HpPa¹, Aib²' ^π)hGIP(l -3O)-NH₂ (SEQ ID NO:45);

(4HpPa¹, Aib², Nle¹⁴)hGEP(l -3O)-NH₂ (SEQ ID NO:46); (4HpPa¹, Aib²)hGIP(l -3O)-NH₂ (SEQ ID NO:47);

(4HpPa¹, 4Hyp³, A6c⁷)hGIP(l-42)-OH (SEQ ID NO:48);

(4HpPa¹, hPro³, A6c⁷)hGIP(l-42)-OH (SEQ ID NO:49);

(4Hppa', Aib², hPro³, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:50);

(His¹, Aib²' ¹³, Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:51); (3,5Br-TyT¹, Aib²' ¹³, Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:52);

(His¹, Aib², A5C¹¹, Nle'⁴)hGIP(l-42)-OH (SEQ ID NO:53);

(3,5Br-Tyr', Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:54);

(3Cl-TyT¹, Aib², A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:55);

(3Br-TyT¹, Aib², A5c^u, Nle¹⁴)hGE?(l-42)-OH (SEQ ID NO:56); (31-Tyr¹, Aib², A5c^π, Nle'⁴)hGIP(l-42)-OH (SEQ ID NO:57);

(3,51-Tyr¹, Aib², A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:58);

(4NH₂-PlIe¹, Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:59);

(hTyr¹, Aib², A5c", Nle¹⁴)hGD?(l-42)-OH (SEQ ID NO:60);

(Cpa¹, Aib², A5c^π, Nle^M)hGIP(l-42)-OH (SEQ DD NO:61); (4NH₂CH₂-PlIe¹, Aib², A5c", Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:62);

(3,4,5F-PlIe¹, Aib², A5c^π, Nle^I4)hGIP(l-42)-OH (SEQ ID NO:63);

(3F-PlIe¹, Aib², A5cⁿ, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:64);

(3,4F-PlIe¹, Aib², A5cⁿ, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:65);

(3,5F-Phe', Aib², A5c^u, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:66); (3OH-Phe', Aib², A5c^u' ⁴¹)hGD?(l-42)-OH (SEQ ID NO:67);

(3OH-TyT¹, Aib², A5c"'⁴¹)hGIP(l-42)-OH (SEQ ID NO:68);

(3MeO-TyT¹, Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ DD NO:69);

[Tyr(Ac)¹, Aib², A5c"' ⁴¹]hGIP(l-42)-OH (SEQ DD NO:70);

(2,6Me-TyT¹, Aib², A5cⁿ' ⁴¹)hGIP(l-42)-OH (SEQ DD NO:71); [TyT(Me)¹, Aib², A5c^π'⁴¹]hGD^>(l-42)-OH (SEQ DD NO:72);

(4F-Phe', Aib², A5c"' ⁴¹)hGD^>(l-42)-OH (SEQ DD NO:73);

(4PaI¹, Aib², A5c"'⁴¹)hGIP(l-42)-OH (SEQ DD NO:74);

(3PaI¹, Aib², A5c"'⁴¹)hGIP(l-42)-OH (SEQ DD NO:75);

(Taz¹, Aib², A5c"' ⁴¹)hGD^>(l-42)-OH (SEQ DD NO:76); (3NO₂-TyT¹, Aib², A5c^π' ⁴¹)hGrP(l-42)-OH (SEQ DD NO:77);

(3Thi', Aib², A5c¹¹'⁴¹)hGπ⁾(l-42)-OH (SEQ DD NO:78);

(4CN-Phe', Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ DD NO:79); (3F-Tyr'_; GIy², A5c^u' ⁴⁰)hGIP(l-42)-OH (SEQ ID NO:80);

[TyT¹^-(CH₂-NH)GIy², A5c^u'⁴¹]hGIP(l-42)-OH (SEQ ID NO:81);

(3F-Phe', Aib², A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO:82);

OCl-Phe¹, Aib², A5c"' ⁴¹)hGIP(l-42)-OH (SEQ ID NO:83); (3Br-PlIe¹, Aib², A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO:84);

(3C1-Tyr', Aib², A5c^{π> 41})hGIP(l-42)-OH (SEQ ID NO:85);

(3Br-TyT¹, Aib², A5c^u'⁴¹)hGIP(l-42)-OH (SEQ ED NO:86);

(β-Tyr¹, Aib², A5c^u' ⁴¹)hGIP(l-42)-OH (SEQ ID NO:87); Aib², A5c^{11 41})hGIP(l-42)-OH (SEQ ID NO:88); (2F-TyT¹, Aib², A5c^{l ll 41})hGIP(l-42)-OH (SEQ ID NO:89);

(αMe-Tyr¹, Aib², A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO:90);

(3NH₂-TyT¹, Aib², A5c^u' ⁴¹)hGIP(l-42)-OH (SEQ ID NO:91);

(2PaI¹, Aib², A5c^π'⁴¹)hGIP(l-42)-OH (SEQ ID NO:92);

[3(HO-CH₂)TyT¹, Aib², A5c^{11 41}]hGIP(l-42)-OH (SEQ ID NO:93); (2,6Me-TyT¹, Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:94);

(2,6Me-TyT¹, Aib², A5cⁿ' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:95);

(2,6Me-TyT¹, Aib², A5c", NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:96);

(Ac-A6c⁷)hGIP(7-42)-OH (SEQ ID NO:97);

[Ac-A6c⁷, Cys(Psu)⁴⁰]hGIP(7-42)-OH (SEQ ID NO:98); [Ac-A6c⁷, Cys(Psu)³⁹]hGB?(7-42)-OH (SEQ ID NO:99);

[Ac-A6c⁷, Cys(Psu)³⁸]hGIP(7-42)-OH (SEQ ID NO: 100);

[Ac-A6c⁷, Cys(Psu)³⁶]hGE?(7-42)-OH (SEQ ID NO:101);

[Ac-A6c⁷, Cys(Psu)³⁵]hGD?(7-42)-OH (SEQ ID NO: 102);

[Ac-A6c⁷, Cys(Psu)³⁴]hGIP(7-42)-OH (SEQ ID NO: 103); [Ac-A6c⁷, Cys(Psu)³³]hGIP(7-42)-OH (SEQ ID NO: 104);

[Ac-A6c⁷, Cys(Psu)³²]hGIP(7-42)-OH (SEQ ID NO: 105);

[Ac-A6c⁷, Cys(Psu)³¹]hGIP(7-42)-OH (SEQ ID NO: 106);

[Ac-A6c⁷, Cys(Psu)³⁷]hGIP(7-42)-OH (SEQ ID NO: 107);

[Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂),₂-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 108); [Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ BD NO: 109);

[A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 110);

[CH₃-(CH₂)₈-C(O)-A6c⁷, Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 111);

[Ac-A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 112);

[A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 113); [CH₃-(CH₂)₄-C(O)-A6c⁷, Orn³¹(N-C(O)-(CH₂)₄-CH₃)]hGIP(7-42)-OH (SEQ DD NO: 114);

[Ac-A6c⁷, Orn³⁴(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 115);

[A6c⁷, Orn³⁴(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 116); [CH₃-(CH₂)₈-C(O)-A6c⁷, Om³⁴(N-C(O)-(CH₂)₈-CH₃)]hGIP(7-42)-OH (SEQ ID NO: 117);

[Ac-A6c⁷, Cys(Hsu)³¹]hGIP(7-42)-OH (SEQ ID NO:118);

[A6c⁷, Cys(Hsu)³¹]hGIP(7-42)-OH (SEQ ID NO: 119);

(Ac-A6c⁷, 2Nal³¹)hGIP(7-42)-OH (SEQ ID NO: 120); (Ac-A6c⁷, D-2Nal³¹)hGIP(7-42)-OH;

(Ac-4Hyp³, A6c⁷)hGIP(3-42)-OH (SEQ ID NO:121);

(Ac-A6c⁷, Gln⁴³)hGIP(7-43)-OH (SEQ ID NO: 122);

[Ac-A6c⁷, Cys(Psu)³¹]hGIP(7-34)-NH₂ (SEQ ID NO: 123);

[Ac-Aόc⁷, Cys(Psu)³¹]hGIP(7-31)-NH₂ (SEQ ID NO: 124); [Ac-Phe⁶, A6c⁷, Cys(Psu)³¹]hGIP(6-42)-OH (SEQ ID NO: 125);

[A6c⁷, Cys(Psu)³¹]hGIP(6-42)-OH (SEQ ID NO: 126);

(Ac-Phe⁶, A6c⁷)hGIP(6-30)-NH₂ (SEQ ID NO: 127);

[Ac-Phe⁶, A6c⁷, Cys(Psu)³¹]hGIP(6-31)-NH₂ (SEQ ID NO: 128);

[A6c⁷, Cys(Psu)³¹]hGIP(6-31)-NH₂ (SEQ ID NO: 129); (A5c⁷, Nle¹⁴)hGIP(6-30)-NH₂ (SEQ ID NO: 130);

(A6c⁷, Nle¹⁴)hGIP(6-30)-NH₂(SEQ ID NO: 131);

(Aib¹¹, Nle¹⁴)hGIP(6-30)-NH₂ (SEQ ID NO: 132);

[Ac-Asp⁹, Cys(Psu)³³]hGIP(9-42)-OH (SEQ ID NO: 133);

[Orn³¹(N-C(O)-(CH₂)₈-CH₃)]hGIP(8-42)-OH (SEQ ID NO:134); [Chc-Ser⁸, Cys(Psu)³¹]hGIP(8-42)-OH (SEQ ID NO: 135);

[CH₃-(CH₂)₄-C(O)-Ser⁸, Cys(Psu)³¹]hGIP(8-42)-OH (SEQ ED NO: 136); 4Hyp³, A6c⁷)hGIP(2-42)-OH (SEQ ID NO: 137);

(4Hppa², Pro³, Nle^M)hGIP(2-42)-OH (SEQ ID NO: 138);

(4Hppa², Aib¹³)hGB?(2-42)-OH (SEQ ID NO: 139); (4Hppa², A6c^I4)hGIP(2-42)-OH (SEQ ID NO: 140);

(4Hppa², A6c^π)hGIP(2-42)-OH (SEQ ID NO:141);

(Aib²' ")hGIP(l-42)-OH (SEQ ID NO: 142);

(Aib^{2 9})hGIP(l-42)-OH (SEQ ID NO:143);

(Aib^{2> 7})hGIP(l-42)-OH (SEQ ID NO: 144); (Aib^{2 5})hGIP(l-42)-OH (SEQ ID NO: 145);

(Aib², A5c⁵)hGIP(l-42)-OH (SEQ ID NO: 146);

(Aib², A5c⁷)hGIP(l-42)-OH (SEQ ID NO: 147);

(Aib², A5c¹²)hGIP(l-42)-OH (SEQ DD NO: 148);

(Aib²- ¹²)hGIP(l-42)-OH (SEQ ID NO: 149); (Aib^{2l 8})hGIP(l-42)-OH (SEQ ID NO: 150);

(Aib^{2> 4})hGEP(l-42)-OH (SEQ ID NO: 151);

(Aib², A5c⁵)hGIP(l -3O)-NH₂ (SEQ ID NO: 152); (Aib², A5c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO: 153);

(Aib², A5c¹²)hGIP(l -3O)-NH₂ (SEQ DD NO: 154);

(Aib²' ⁴)hGIP(l -3O)-NH₂ (SEQ TD NO:155);

(Aib²' ⁵)hGIP(l -3O)-NH₂ (SEQ ID NO: 156); (Aib²' ⁷)hGIP(l -3O)-NH₂ (SEQ ID NO: 157);

(Aib²' ⁸)hGIP(l -3O)-NH₂ (SEQ ID NO: 158);

(Aib²' ⁹)hGIP(l -3O)-NH₂ (SEQ ID NO: 159);

(Aib²' ^π)hGIP(l-30)-NH₂ (SEQ ID NO: 160);

(Aib²' ¹²)hGIP(l -3O)-NH₂ (SEQ ID NO: 161); (Aib²' ¹³, A6c⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 162);

(Aib²' ³¹, A6c⁷)hGIP(l-42)-OH (SEQ ID NO: 163);

(Aib²'⁴¹, A6c⁷)hGIP(l-42)-OH (SEQ ID NO: 164);

(Aib²' ³¹, A6c⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 165);

(Aib²'⁴¹, A6c⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 166); (Aib², A6c⁷'²⁶, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 167);

(Aib², A6c⁷'²⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ DD NO: 168);

(Aib², A6c⁷'⁴⁰, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:169);

(Aib², A6c⁷'⁴¹, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 170);

(Aib²'²⁸, A6c⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 171); (Aib², A6c⁷, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:172);

(Aib², A5c⁷, Nle¹⁴)hGIP(l-30)-NH₂ (SEQ ID NO: 173);

(Aib^{2 11}, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 174);

(A5c²' ⁷, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 175);

(Aib², A5c⁷' ^M)hGIP(l-30)-NH₂ (SEQ ID NO: 176); (A6c²' ⁷, Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO: 177);

(Aib², A6c⁷' ¹⁷, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 178);

(Aib²' ", A6c¹⁴)hGIP(l-30)-NH₂ (SEQ ID NO:179);

(Aib², A6c⁷' ¹⁴)hGD?(l -3O)-NH₂ (SEQ ID NO: 180);

(A5c², Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 181); (Aib²' ", A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO: 182);

(Aib², A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO: 183);

(Aib², A6c⁷)hGIP(l-42)-OH (SEQ ID NO: 184);

(Aib², A5c⁷, A6c^M)hGIP(l-42)-OH (SEQ ID NO: 185);

(Aib^{2 11}, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO: 186); (Aib², A5c")hGIP(l -3O)-NH₂ (SEQ ID NO: 187);

(Aib²' ¹³)hGIP(l -3O)-NH₂ (SEQ DD NO: 188);

(Aib², A5c^π, A6c¹⁴)hGIP(l-30)-NH₂ (SEQ DD NO: 189); (Aib²' ¹³, Nle^l4)hGIP(l-30)-NH₂ (SEQ ID NO: 190);

(Aib², A5c", Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:191);

(Aib², A6c^{7 14})hGEP(l-42)-OH (SEQ ID NO: 192);

(Aib², A6c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO: 193); (Aib², A5c")hGIP(l-42)-OH (SEQ ED NO: 194);

(Aib², A5c^π, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:195);

(Aib², A6c⁷, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 196);

(A5c²' ⁷, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO: 197);

(Aib²- ¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 198); (Aib², A5c⁷, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO: 199);

(Aib², A5c⁷' ¹⁴)hGEP(l-42)-OH (SEQ ED NO:200);

(Aib²' ¹³)hGEP(l-42)-OH (SEQ ED NO:201);

(Aib², A5c^π, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO:202);

(Pro³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:203); (hPro³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:204);

(Dhp³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:205);

(hPro³, Aib¹³)hGEP(l-42)-OH (SEQ ED NO:206);

(Tic³, Aib¹³)hGEP(l-42)-OH (SEQ ED NO:207);

(4Hyp³, Aib¹³)hGEP(l-42)-OH (SEQ ED NO:208); (4Hyp³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:209);

(Tic³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:210);

(3Hyp³, Aib¹³, Nle¹⁴)hGEP(l-42)-OH (SEQ ED NO:211);

(Tic³, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO:212);

(hPro³, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO:213); [Aib², A6c⁷, Cys(Psu)⁴¹]hGIP(l-42)-OH (SEQ ED NO:214);

(hPro³, A5c")hGIP(l-42)-OH (SEQ ED NO:215);

(Pro³, Aib^l3)hGEP(l-42)-OH (SEQ ED NO:216);

(Pro³, A5c^{7 14})hGEP(l-42)-OH (SEQ ED NO:217);

(Pro³, A5c")hGIP(l-42)-OH (SEQ ED NO:218); [Aib², A6c⁷, Cys(Psu)⁴⁰]hGEP(l-42)-OH (SEQ ED NO:219);

[Aib², A6c⁷, Cys(Psu)³⁹]hGEP(l-42)-OH (SEQ ED NO:220);

[Aib², A6c⁷, Cys(Psu)³⁸]hGEP(l-42)-OH (SEQ ED NO:221);

[Aib², A6c⁷, Cys(Psu)³⁶]hGEP(l-42)-OH (SEQ ED NO:222);

(Tic³, A5c^u)hGEP(l-42)-OH (SEQ ED NO:223); (hPro³, A5c^π, A6c¹⁴)hGIP(l-42)-OH (SEQ ED NO:224);

(4Hyp³, A6c¹⁴)hGEP(l-42)-OH (SEQ ED NO:225);

[Aib², A6c⁷, Cys(Psu)³⁵]hGEP(l-42)-OH (SEQ ED NO:226); [Aib², A6c⁷, Cys(Psu)³⁴]hGIP(l-42)-OH (SEQ ID NO:227);

(4Hyp³, A5c^π)hGIP(l-42)-OH (SEQ ID NO:228);

(4Hyp³, A5cⁿ, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:229);

(Tic³, A5c^π, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:230); [Aib², A6c⁷, Cys(Psu)³¹]hGIP(l-42)-OH (SEQ ID NO:231);

(Pro³, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:232);

(Pro³, A5c^π, Nle¹⁴)hGIP(l-42)-OH (SEQ ID NO:233);

(Aib², A6c⁷, Gln⁴³)hGIP(l-43)-OH (SEQ ID NO:234);

[Aib², A5c⁷, Cys(Psu)³²]hGIP(l-42)-OH (SEQ ID NO:235); [Aib², A5c⁷, Cys(Psu)⁴³]hGIP(l-43)-OH (SEQ ID NO:236);

(Pro³, A5c", A6c¹⁴)hGIP(l-30)-NH₂ (SEQ ID NO:237);

(Pro³, A6c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO:238);

(Pro³, A5c")hGIP(l-30)-NH₂ (SEQ ID NO:239);

[Aib², A6c⁷, Cys(Psu)³³]hGIP(l-42)-OH (SEQ ID NO:240); [Aib², A6c⁷, Cys(Psu)³⁷]hGIP(l-42)-OH (SEQ ID NO:241);

(4Hppa', Aib¹³)hGIP(l-42)-OH (SEQ ID NO:242);

(Pro³, A5cⁿ, A6c¹⁴)hGIP(l-42)-OH (SEQ ID NO:243);

[Orn¹(N-C(O)-(CH₂)₁₂-CH₃), A6c⁷]hGIP(l-42)-OH (SEQ ID NO:244);

(D-AIa², A5c"'⁴⁰)hGIP(l-42)-OH; (D-AIa², A5c", His⁴³)hGIP(l-43)-OH;

(D-AIa², A5cⁿ' ⁴¹)hGIP(l-42)-OH;

(D-AIa², Aόc¹¹' ^{14 41})hGIP(l-42)-OH;

(Aib²' ¹³, Pro³, Nle¹⁴)hGIP(l-30)-NH₂ (SEQ ID NO:245);

(Aib², Pro³, A6c⁷)hGIP(l -3O)-NH₂ (SEQ ID NO:246); (Aib², Pro³, A5c^π)hGIP(l -3O)-NH₂ (SEQ ID NO:247);

(Aib², Pro³, A5c", Nle¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:248);

(Aib², Pro³, A5c", A6c¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:249);

(NMe-Tyr¹, Aib², A5c", Nle^I4)hGIP(l-42)-OH (SEQ ID NO:250);

(GIy², A6c"' ^{l4 4l})hGIP(l-42)-OH (SEQ ID NO:251); (GIy², Aib¹³, A5c⁴⁰)hGIP(l-42)-OH (SEQ ID NO:252);

(GIy², A5c^{11> 41})hGIP(l-42)-OH (SEQ ID NO:253);

(GIy², A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO:254);

(3F-Phe', Aib², A5c^π' ^{14> 41})hGIP(l-42)-OH (SEQ ID NO:255);

(3F-PlIe¹, Aib², A5c^{11 41}, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:256); (3F-PlIe¹, Aib², A5c"'⁴¹, His⁴³)hGIP(l-43)-OH (SEQ ID NO:257);

(3F-Phe', Aib², A5c^{Hl 14> 4}\ His⁴³)hGIP(l-43)-OH (SEQ ID NO:258);

(GIy², A5c", NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:259); (D-AIa², A5c^π, NIe¹⁴, His⁴³)hGIP(l-43)-OH;

(D-AIa², A5c"' ¹⁴, His⁴³)hGIP(l-43)-OH;

(D-AIa², A5c"' ^l4)hGIP(l -3O)-NH₂;

(D-AIa², A5c", His³¹)hGIP(l-31)-NH₂; (Aib², A5c^π' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:260);

(A5c")hGIP(l -3O)-NH₂ (SEQ ID NO:261);

(A5cⁿ, His³¹)hGIP(l-31)-NH₂ (SEQ ID NO:262);

(A5c^u' ¹⁴)hGIP(l -3O)-NH₂ (SEQ ID NO:263);

(A5c^{I 1> 4}\ Cys³²)hGIP(l-42)-NH₂ (SEQ ID NO:264); (A5c^{1 M1}, Cys³³)hGIP(l-42)-NH₂ (SEQ ID NO:265);

(A5c^{11 41}, Cys⁴³)hGIP(l-43)-NH₂ (SEQ ID NO:266);

[A5c", Orn³²(N-C(O)-(CH₂)₁₀-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:267);

[A5c", Orn³³(N-C(O)-(CH₂)₁₀-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:268);

[A5c^π, Lys⁴³(N-C(O)-(CH₂)_l0-CH₃)]hGIP(l-43)-OH (SEQ ID NO:269); [A5c^π, Cys³²(succinimide-N-(CH₂)₁₁-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:270);

[A5c^u, Cys³³(succinimide-N-(CH₂)π-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:271);

[A5c^π, Cys⁴³(succinimide-N-(CH₂)_u-CH₃)]hGIP(l-43)-OH (SEQ ID NO:272);

[A5cⁿ, Lys⁴³(N-C(O)-(CH₂)₁₄-CH₃)]hGIP(l-43)-OH (SEQ ID NO:273);

[A5c^π, Orn³²(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:274); [A5c", Orn³³(N-C(O)-(CH₂)₁₄-CH₃), His⁴³]hGIP(l-43)-OH (SEQ ID NO:275);

(3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, His⁴³)hGIP(l-43)-OH;

(3Cl-TyT¹, D-AIa², A5c^π' ¹⁴, His⁴³)hGIP(l-43)-OH;

(3C1-Tyτ', Aib², A5c^u' ^M, His⁴³)hGIP(l-43)-OH (SEQ ID NO:276);

(3Cl-TyT¹, Aib², A5c^π, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:277); [3Cl-TyT¹, Aib², A5c^π, NIe¹⁴, Orn⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH (SEQ ID NO:278);

[3Cl-TyT¹, Aib², A5c^π, NIe¹⁴, Cys⁴³(succinimide-N-(CH₂), ,-CH₃)]hGIP(l-43)-OH

(SEQ ID NO:279);

[3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, Orn⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

[3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, Cys⁴³(succinimide-N-(CH₂)_n-CH₃)]hGIP(l-43)-OH; [3Cl-TyT¹, D-AIa², A5c^π' ¹⁴, Orn⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

[3Cl-TyT¹, D-AIa², A5c^{π> M}, Cys⁴³(succinimide-N-(CH₂),,-CH₃)]hGIP(l-43)-OH;

(3Bτ-Tyr', Aib², A5c^u, NIe¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:280);

(3Br-TyT¹, Aib², A5c"' ¹⁴, His⁴³)hGIP(l-43)-OH (SEQ ID NO:281);

(3MeO-TyT¹, Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:282); (3MeO-TyT¹, Aib², A5c^{π> l4}, His⁴³)hGIP(l-43)-OH (SEQ ID NO:283);

(3MeO-TyT¹, Aib², A5c"' ¹⁴' ⁴¹, His⁴³)hGIP(l-43)-OH (SEQ ID NO:284);

(4CF₃-Phe', Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:285); (7HO-TiC¹, Aib², A5c^u, His⁴³)hGIP(l-43)-OH (SEQ ID NO:286);

(4Me-Phe', Aib², A5c^π, His⁴³)hGIP(l-43)-OH (SEQ ID NO:287);

(4CN-Fhe\ Aib², A5cⁿ, His⁴³)hGIP(l-43)-OH (SEQ ID NO:288);

(hTyr¹, Aib², A5c", His⁴³)hGIP(l-43)-OH (SEQ ID NO:289); [3Cl-TyT¹, D-AIa², A5c^π, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

[3Cl-TyT¹, D-AIa², A5c^u' ¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH;

[3Cl-TyT¹, Aib², A5c^π, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)₁₀-CH₃)]hGIP(l-43)-OH (SEQ ID NO:290);

[3Cl-TyT¹, Aib², A5c^{π> 14}, Lys⁴³(N-C(0)-(CH₂),o-CH₃)]hGIP(l-43)-OH (SEQ ID NO:291);

[3C1-Tyr', Aib², A5c^π, NIe¹⁴, Cys⁴³]hGIP(l-43)-OH (SEQ ID NO:293); [3C1-Tyr', D-AIa², A5cⁿ, NIe¹⁴, Cys⁴³(succinimide)]hGIP(l-43)-OH;

[3Cl-TyT¹, D-AIa², A5cⁿ' ¹⁴, Cys⁴³(succinimide)]hGIP(l-43)-OH;

[Aib², A5cⁿ, NIe¹⁴, Lys⁴³(N-C(O)-(CH₂)_l0-CH₃)]hGIP(2-43)-OH (SEQ ID NO:294); hGIP(l-42)-NH₂ (SEQ ID NO:2); hGIP(l-30)-NH₂ (SEQ ID NO:3); hGIP(l-30)-OH (SEQ ID NO:4); hGIP(7-30)-NH₂ (SEQ ID NO:5); hGIP(7-30)-OH (SEQ ID NO:6); hGIP(6-30)-NH₂ (SEQ ID NO:7); hGIP(6-30)-OH (SEQ ID NO: 8); (Pro³)hGIP(l-42)-OH (SEQ ID N0:9);

(Pro³)hGIP(l-42)-NH₂ (SEQ DD NO: 10);

(Aib²)hGIP(l-42)-OH (SEQ ID NO:11);

(Aib²)hGIP(l-42)-NH₂ (SEQ DD NO: 12);

(D-Ala²)hGIP( 1 -42)-OH; (D-Ala²)hGIP(l-42)-NH₂;

(Aib²)hGIP(l -3O)-OH (SEQ ID NO: 13);

(Aib²)hGIP(l -3O)-NH₂ (SEQ ID NO: 14);

(D-Ala²)hGIP(l -3O)-NH₂;

(D-Ala²)hGIP(l -3O)-OH.

3. The pharmaceutical composition according to claim 2, wherein said GD? compound further comprises a covalently linked PEG moiety.

4. The pharmaceutical composition according to claim 3, wherein said PEG moiety is linked to the GIP compound via a Cys(maleimide), hCys(maleimide), or Pen(maleimide) linker, to form Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG).

5. The pharmaceutical composition according to claim 4, wherein PEGylation occurs at any one of amino acid residue positions 16, 30, and 31-43, whereby Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of amino acid residue positions 16, 30, and 31-43.

6. The pharmaceutical composition according to claim 5, wherein PEGylation occurs at any one of amino acid residue positions 32, 33 and 43, whereby Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of amino acid residue positions 32, 33 and 43.

7. The pharmaceutical composition according to claim 6, wherein said PEG moiety has average molecular weight of from about 2,000 to about 80,000.

8. The pharmaceutical composition according to claim 7, wherein said PEG moiety is selected from the group consisting of 5K PEG, 1 OK PEG, 2OK PEG, 30K PEG, 4OK PEG, 50K PEG, and 6OK PEG, to form Cys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG), Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG), Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG), Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG), hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG), hCys(succinimide-N-30K PEG), hCys(succinimide-N-40K PEG), hCys(succinimide-N-50K PEG), hCys(succinimide-N-60K PEG), Pen(succinimide-N-5K PEG), Pen(succinimide-N-10K PEG), Pen(succinimide-N-20K PEG), Pen(succinimide-N-30K PEG), Pen(succinimide-N-40K PEG), Pen(succinimide-N-50K PEG), or Pen(succinimide-N-60K PEG).

9. A pharmaceutical composition according to any one of claims 4-8, wherein said succinimide-N-PEG is linear.

10. A pharmaceutical composition according to claim 9, wherein said linear succinimide- N-PEG is succinimide-N-(CH₂)₂-C(O)NH-(CH₂)₃-PEG.

11. A pharmaceutical composition according to any one of claims 4-8, wherein said succinimide-N-PEG is branched.

12. A pharmaceutical composition according to claim 11, wherein said branched succinimide-N-PEG is succinimide-N-(CH₂)₂-C(O)NH-(CH₂)₃-O-CH₂-CH(PEG)-CH₂-PEG.

13. The pharmaceutical composition according to claim 12, further comprising a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to any one of claims 1-13, further comprising a divalent metal or divalent metal salt.

15. The pharmaceutical composition according to claim 14, wherein said divalent metal is zinc, copper, calcium, or magnesium.

16. The pharmaceutical composition according to claim 14, wherein said composition contains a divalent metal salt selected from the group consisting Of ZnCl₂, ZnAc₂, (C₆H₅Ov)₂Zn₃, CuCl₂, CuAc₂, (C₆H₅O₇)₂Cu₃, MgCl₂, MgAc₂, (C₆H₅O₇)₂Mg3, CaCl₂, CaAc₂, and (C₆H₅Ov)₂Ca₃.

17. The pharmaceutical composition according to claim 14, wherein said divalent metal salt is hydrated.

18. The pharmaceutical composition according to claim 15, claim 16 or claim 17, further comprising water.

19. The pharmaceutical composition according to any one of claims 1-18, further comprising non-aqueous medium.

20. The pharmaceutical composition according to any one of claims 1-19, wherein said

GIP compound is present in an aqueous medium with pH between 2.0 and 10.5, preferably between 3 and 8.

21. The pharmaceutical composition according to any one of claims 1 -20, wherein said GIP cmpound is present in a concentration of about from 0.001 to 500 mg/ml, preferably about from

0.1 to 400 mg/ml.

22. The pharmaceutical composition according to any one of claims 1-21, further comprising a preservative.

23. The pharmaceutical composition according to claim 22, wherein said preservative is selected from the group consisting of m-cresol, phenol, benzyl alcohol, and methyl paraben.

24. The pharmaceutical composition according to claim 23, wherein said preservative is present in a concentration of about from 0.01 mg/ml to 100 mg/ml.

25. The pharmaceutical composition according to any one of claims 1-24, further comprising an isotonic agent.

26. The pharmaceutical composition according to claim 25, wherein said isotonic agent is present in a concentration of about from 0.01 mg/ml to 100 mg/ml.

27. The pharmaceutical composition according to any one of claims 1-26, wherein said zinc is present in a concentration of about from 0.0005 mg/ml to 50 mg/ml.

28. The pharmaceutical composition according to any one of claims 1-27, further comprising a stabilizer.

29. The pharmaceutical composition according to claim 28, wherein said stabilizer is selected from the group consisting of imidazole, arginine, and histidine.

30. The pharmaceutical composition according to any one of claims 1-29, further comprising a surfactant.

31. The pharmaceutical composition according to any one of claims 1 -30, further comprising a chelating agent.

32. The pharmaceutical composition according to any one of claims 1-31, further comprising a buffer.

33. The pharmaceutical composition according to claim 32, wherein said buffer is selected from the group consisting of Tris, ammonium acetate, sodium acetate, glycine, aspartic acid, and Bis-Tris.

34. The pharmaceutical composition according to any one of claims 1-33, further comprising a basic polypeptide.

35. The pharmaceutical composition according to claim 34, wherein said basic polypeptide is selected from the group consisting of polylysine, polyarginine, polyornithine, protamine, putrescine, spermine, spermidine, and histone.

36. The pharmaceutical composition according to any one of claims 1-35, further comprising alcohol, monosaccharide, or disaccharide.

37. The pharmaceutical composition according to claim 36, wherein said alcohol, monosaccharide, or disaccharide is selected from the group consisting of methanol, ethanol, propanol, glycerol, trehalose, mannitol, glucose, erythrose, ribose, galactose, fructose, maltose, sucrose, and lactose.

38. A method of eliciting an agonist effect from a GEP receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

39. A method of eliciting an antagonist effect from a GIP receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

40. A method for treating conditions or diseases mediated by GEP-receptor binding, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

41. The method of claim 40, wherein said condition or disease mediated by GEP-receptor binding is selected from the group consisting of type 1 diabetes, type 2 diabetes, obesity, insulin resistance, glucose intolerance, fatty liver, glucagonomas, secretory disorders of the airway, metabolic disorders, arthritis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake and/or losing body weight is desired.

42. A method for treating diabetes, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

43. The method of claim 42, wherein said diabetes is type 2 diabetes.

44. A method of treating diabetes-related disorders, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

45. The method of claim 44, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.

46. A method of treating or preventing secondary causes of diabetes, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

47. The method of claim 46, wherein said secondary cause is selected from the group consisting of glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.

48. A method of treating obesity, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

49. A method of stimulating insulin secretion in a subject in need thereof by administering to said subject a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-37.

50. Use of a pharmaceutical composition of any one of claims 1-37 for the manufacture of a medicament for GIP-receptor binding for the prevention or treatment of diseases or conditions related to impaired binding of GIP-receptor analogues.

51. Use according to claim 50 for the manufacture of a medicament for the prevention or treatment of pancreatic beta cell apoptosis.

52. Use according to claim 50 for the manufacture of a medicament for the potentiation of glucose dependent proliferation of pancreatic beta cells.