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WO1991016923A1 - Nouveaux analogues grf synthetiques - Google Patents

Nouveaux analogues grf synthetiques Download PDF

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Publication number
WO1991016923A1
WO1991016923A1 PCT/US1991/003053 US9103053W WO9116923A1 WO 1991016923 A1 WO1991016923 A1 WO 1991016923A1 US 9103053 W US9103053 W US 9103053W WO 9116923 A1 WO9116923 A1 WO 9116923A1
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WO
WIPO (PCT)
Prior art keywords
ala
peptide
leu
grf
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1991/003053
Other languages
English (en)
Inventor
David H. Coy
William Murphy
Simon J. Hocart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tulane University
Original Assignee
Tulane University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tulane University filed Critical Tulane University
Priority to JP3509839A priority Critical patent/JPH06502618A/ja
Priority to AU78822/91A priority patent/AU651976B2/en
Publication of WO1991016923A1 publication Critical patent/WO1991016923A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel peptides having therapeutic utility. More specifically, the invention relates to peptide analogs of the naturally occurring peptide, growth hormone-releasing factor (GRF). The invention also relates to therapeutic compositions
  • Growth hormone (GH or somatotropin) is a 191- amino acid peptide which is secreted by the anterior
  • Growth hormone itself does not actually promote growth directly but acts by simulating the production of one of the many true growth factors such as the somatomedins produced by the liver. The ultimate effects of growth hormone are widespread however. On a gross level, this hormone affects the skeleton, connective tissue, muscles and viscera. On a molecular level, the metabolic effects of growth hormone and somatomedins include stimulation of nucleic acid and protein synthesis, induction of positive nitrogen balance, stimulation of lipolysis, and a decrease in urea excretion.
  • hypothalamus and is transported to the pituitary by portal circulation.
  • other cells of the body such as pancreatic tumor cells, may also produce this hormone.
  • Growth hormone releasing factor in humans is a peptide 44 amino acids in length of which the first 29 contain the full biological activity. Similar peptides have also been isolated from cow, rat, sheep and pig, and their sequences identified (Esch et al., Biochem. Biophys. Res. Commun.
  • Certain peptide hormones i.e., those in which one face of the molecule has preferentially hydrophobic residues, while the other face contains a primarily hydrophilic domain, may have their activity enhanced by optimization of this amphiphilic character.
  • GRF has been noted as having substantial amphiphilic potential, based on observations of its binding to single bilayer phospholipid vesicles, and formation of a monolayer at the air-water interface (Kaiser et al., Science
  • the present invention relates to a group of novel peptides which are analogues of the native hormone GRF.
  • the novel hormones are characterized by substitution of the Asn normally at the number 8 position in the native molecule with amino acids which are conducive to ⁇ -helix formation.
  • the invention relates to peptides comprising the formula: R 1 - R 2 - R 3 - Ala - lle - Phe - R 7 - R 8 - R 9 -
  • R 10 - Arg - R 12 - R 13 - R 14 - R 15 - Gln - R 17 - R 18 - Ala - Arg - R 21 - Leu - R 23 - R 24 - R 25 - R 26 - R 27 - R 28 - R 29
  • R 1 is des-amino-Tyr, or A-R 1 , in which A is lower alkyl, lower cycloalkyl, benzyl or lower acyl and R 1 is Tyr,
  • R 2 is Ala, D-Ala, D-NMA, or D-Arg;
  • R 3 is Asp or D-Asp
  • R 7 is Thr, Aib, NO 2 , Leu, Trp, ⁇ -Nal, or p-X-Phe, in which
  • X H, F, Cl, Br, NO 2 , or Me;
  • R 8 is Ala, Aib, Leu, Trp, ⁇ -Nal, or p-X-Phe, in which X is H, F, Cl, Br, NO 2 , or Me;
  • R 9 is Ser, Ala , Aib , Leu, Trp , ⁇ -Nal or p-X-Phe , in which X is H, F, Cl, Br, NO 2 , or Me
  • R 10 is Tyr or D-Tyr
  • R 12 and R 21 are Lys, Arg, or N ⁇ -B-Lys, in which B is lower alkyl or cycloalkyl, and may be the same or different R 13 is lie or Val
  • R 14 is Leu or D-Leu
  • R 15 Gly, Ala, Leu, Asn, Gin or Aib
  • R 17 is Leu or D-Leu
  • R 18 is Tyr or Ser
  • R 23 is Leu or d-Leu
  • R 25 is Glu, Asp, D-Glu or D-Asp
  • R 26 is lle or Leu
  • R 27 is Met, D-Met, Ala, Nle, lle, Leu, Nva, or Val
  • R 28 is Asn, Ser or des R 28
  • R 29 is Arg, D-Arg or des R 29 ;
  • R 8 is Ala; in a particularly preferred embodiment, R 8 and R 15 are Ala, and most preferably, R 8 , R 9 , and R 15 are Ala.
  • a particularly effective peptide is formed when R 8 , R 9 , and R 15 are Ala, and R 2 is D-Ala.
  • compositions comprising a growth hormone-releasing effective amount of the peptides/salts described above in combination with apharmaceutically acceptable carrier. Also provided is a method of stimulating release of growth hormone by
  • composition of the invention administered to an individual in need of such treatment.
  • Such a method is useful in the treatment of physiological conditions in which release of a growth hormone would be expected to be of benefit.
  • a method of stimulating growth in healthy animals is also provided which comprises administering the
  • compositions of the present invention to such animals.
  • a particularly effective GRF receptor antagonist is produced by combining the specified substitutions at the 8, 9, or 15 positions with a substitution of D-Arg in the R 2 position.
  • Such peptides inhibit the activity of endogenous GRF, and therefore in turn prevent the release of growth hormone.
  • compositions comprising a GRF-antagonistic effective amount of such a peptide, in combination with a pharmaceutically acceptable carrier as well as methods for inhibiting release of growth hormone by administering these compositions to an individual in need of such treatment.
  • the peptides of the present invention are analogues of native GRF which exhibit greater potency than the natural hormone in releasing growth hormone.
  • the increase in potency of these analogues is believed to be due to an enhancement in the ⁇ -helical properties of the N-terminal portion of the GRF molecule.
  • enhancement of the amphiphilic ⁇ -helical properties of the C-terminal region results in increased potency of the peptides, it was not known how such
  • Gin, or Aib preferably Ala
  • a further favorable modification is the
  • substitution at position 9 of one of the same preferred residues used at position 8. The combination of these substitutions at the 8, 9, and 15 position, particularly when they are all Ala substituents, enhances the potency, and when combined with Glu 25 and Leu 26,27 , activity is increased to 33 times that of the native GRF molecule.
  • the preparation of the peptides of the present invention can be accomplished by any of the known methods for peptide synthesis.
  • a preferred method is solid phase synthesis such as described by Merrifield (J. Am. Chem. Soc. 85:2149, 1963).
  • construction of the peptide begins at the C-terminus; an amino-protected amino acid is coupled, by known methods, to an appropriate resin, such as a chloromethylated resin, a benzhydryl-amine resin or a methylbenzhydrylamme resin.
  • an appropriate resin such as a chloromethylated resin, a benzhydryl-amine resin or a methylbenzhydrylamme resin.
  • carbodrimide derivatives such as dicyclohexylcarbodiimide and diisopropylcarbodiimide. Alternately, several aminoacids may be coupled to each other before being added to the solid phase synthesizer. When the sequence has been
  • the entire peptide is cleaved from the resin, and may be purified by routine procedures in the art, such as
  • salts such as acid addition salts and metal complexes
  • salts include hydrochloride, hydrobromide, sulfate, acetate, maleate, benzoate, citrate, tartrate, ascorbate, or phosphate, and metal complexes of iron or zinc.
  • the peptides are preferably administered
  • the peptides will normally be combined with a pharmaceutically acceptable carrier, such as water, or isotonic saline.
  • a pharmaceutically acceptable carrier such as water, or isotonic saline.
  • the peptides may be administered orally in the form of tablets or capsules, which contain the appropriate binders, lubricants and the like.
  • the amount of peptide needed per composition, and/or unit dosage can readily be determined by reference and comparison to known compositions and dosage forms currently in use for GRF peptides. In general terms, however, the dosage range will be between 50 ng - 5 ⁇ g/kg of body weight of the host. The dose will depend upon the mode of administration and the intended result. However, such manipulations are well within the ability of one skilled in the art.
  • this includes for example administration to livestock, such as cattle, chickens, turkeys, pigs, goats, fish, and the like, both to promote growth and also to alter or improve the ratio of protein (muscle) to fat in such animals.
  • the peptides are also useful for the treatment of growth hormone deficiency-related disorders, such as pituitary dwarfism.
  • growth hormone deficiency-related disorders such as pituitary dwarfism.
  • Arg 2 are GRF antagonists and may therefore be used in treatment of conditions caused by excess growth hormone.
  • An example of such a condition is acromegaly, which results in abnormal enlargement of the bones of the face and.
  • the neutralized resin is stirred with Boc-N G - tosyl-
  • Boc-Gln Boc-Gly, Boc-Leu, Boc-Val, Boc-Lys(2-Cl-Z), Boc-
  • Vydac octadecylsilane silica 10-15 ⁇ K
  • This is eluted with a linear gradient of 10-45% acetonitrile in 0.1% trifluoroacetic acid in water.
  • the product is found to be homogeneous by HPLC and
  • the neutralized resin is stirred with Boc-N G - tosyl-
  • the product is found to be homogeneous by hplc and tic. Amino acid analysis of an acid hydrolysate confirms the composition of the octapeptide.
  • a number of the peptides of the present invention were tested in an in vitro assay for their utility to stimulate relase of growth hormone from pituitary cells.
  • the dispersed cells were diluted with sterile- filtered Dulbecco's modified Eagle medium (MEM) (Gibco).
  • the cells were counted with a hemacytometer (approximately 2,000,000 cells per pituitary) and randomly plated at a density of 200,000 cells per well (Costar cluster 24; Rochester Scientific, Rochester, NY). The plated cells were maintained in the above Dulbecco's medium in a humidified atmosphere of 95% air and 5% CO 2 at 37oC for 96 h.
  • glucocorticoids After 3 h at 37oC in an air/carbon dioxide atmosphere (95/5%), the medium was removed and stored at -20oC until assayed for hormone content. 6.2.4. GH RIA
  • GH in plasma and media was measured by a standard double antibody RIA using components generously supplied by
  • N-terminal region i.e., at positions 7 and 10 have an essentially detrimental effect when combined with the

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Biophysics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Luminescent Compositions (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne de nouveaux peptides ayant une utilisation thérapeutique. Plus spécifiquement, l'invention concerne des analogues peptidiques du facteur de libération d'hormone de croissance (GRF) de peptides se produisant naturellement. L'invention concerne également des compositions thérapeutiques contenant ces peptides, et des procédés thérapeutiques utilisant ces peptides pour stimuler la production de l'hormone de croissance in vivo.
PCT/US1991/003053 1990-05-04 1991-04-30 Nouveaux analogues grf synthetiques Ceased WO1991016923A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP3509839A JPH06502618A (ja) 1990-05-04 1991-04-30 新規な合成ｇｒｆ類似物
AU78822/91A AU651976B2 (en) 1990-05-04 1991-04-30 Novel synthetic GRF analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51905490A 1990-05-04 1990-05-04
US519,054 1990-05-04

Publications (1)

Publication Number Publication Date
WO1991016923A1 true WO1991016923A1 (fr) 1991-11-14

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ID=24066591

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/003053 Ceased WO1991016923A1 (fr) 1990-05-04 1991-04-30 Nouveaux analogues grf synthetiques

Country Status (5)

Country Link
EP (1) EP0527914A4 (fr)
JP (1) JPH06502618A (fr)
AU (1) AU651976B2 (fr)
CA (1) CA2082059A1 (fr)
WO (1) WO1991016923A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0514210A3 (en) * 1991-05-15 1993-04-28 The Salk Institute For Biological Studies Grf analogs
WO1994011396A1 (fr) * 1992-11-13 1994-05-26 The Administrators Of The Tulane Educational Fund Agonistes de l'hormone de liberation de l'hormone de croissance
WO1994011397A1 (fr) * 1992-11-13 1994-05-26 The Administrators Of The Tulane Educational Fund Agonistes de somatostatine
WO1995016707A1 (fr) * 1993-12-17 1995-06-22 The Administrators Of The Tulane Educational Fund ANALOGUES DE hGH-RH (1-29)NH2 POSSEDANT UNE ACTIVITE ANTAGONISTE
US5847066A (en) * 1995-04-14 1998-12-08 The Administrators Of The Tulane Educational Fund Analogs of growth hormone-releasing factor
US5854216A (en) * 1994-09-23 1998-12-29 Universite De Montreal Marker for growth hormone-releasing factor receptors
US5942489A (en) * 1996-05-03 1999-08-24 The Administrators Of The Tulane Educational Fund HGH-RH(1-29)NH2 analogues having antagonistic activity
US6057422A (en) * 1998-11-25 2000-05-02 The Administrators Of The Tulane Educational Fund Antagonistic analogs of GH-RH inhibiting IGF-I and -II
WO2000014236A3 (fr) * 1998-09-08 2000-06-02 Theratechnologies Inc Analogues de somatostatine (grf) à activité biologique accrue
US6184208B1 (en) 1994-06-29 2001-02-06 Immunotech Developments Inc. Peptide, a method for its preparation and a pharmaceutical composition containing the peptide
WO2009120831A3 (fr) * 2008-03-28 2009-12-23 The University Of Miami Nouveaux analogues antagonistes substitués n- et c-terminaux de gh-rh
EP2664343A2 (fr) 2008-11-17 2013-11-20 Syntaxin Limited Suppression du cancer
US8691942B2 (en) 2008-03-28 2014-04-08 University Of Miami N- and C- terminal substituted antagonistic analogs of GH-RH
EP3473643A1 (fr) 2008-06-12 2019-04-24 Ipsen Bioinnovation Limited Protéines de fusion pour leur utilisation dans le traitement du cancer
EP3590956A1 (fr) 2008-06-12 2020-01-08 Ipsen Bioinnovation Limited Suppression de maladies neuroendocrines
US11993640B2 (en) 2019-02-08 2024-05-28 The United States Government As Represented By The Department Of Veterans Affairs Treating inflammatory lung disease
US12377135B2 (en) 2019-07-18 2025-08-05 University Of Miami GHRH antagonists for use in a method of treating sarcoidosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649131A (en) * 1984-09-24 1987-03-10 Hoffmann-La Roche Inc. Growth hormone releasing factor analogs
US4689318A (en) * 1985-08-29 1987-08-25 The Salk Institute For Biological Studies GRF analogs

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL86102A (en) * 1987-05-11 1994-04-12 Univ Tulane Alkylated growth hormone-releasing peptides and use thereof
US5262519A (en) * 1991-05-15 1993-11-16 The Salk Institute For Biological Studies GRF analogs XI

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649131A (en) * 1984-09-24 1987-03-10 Hoffmann-La Roche Inc. Growth hormone releasing factor analogs
US4689318A (en) * 1985-08-29 1987-08-25 The Salk Institute For Biological Studies GRF analogs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Biochemical and Biophysical Research Communications, Vol. 49, No. 2, issued 16 December 1987, SATO et al., "Synthesis and in vitro bioactivity of human growth hormone-releasing factor analogs substituted with a single D-amino acid", pp. 531-537, see page 535, table 3. *
Peptide: Chem. Biol., Proceedings American Peptide Symposium, 10th Meeting, issued 1987, FELIX et al., "Synthesis and biological activity of novel linear and cyclic GRF analogs", pp. 465-467, see page 466, table 1. *
See also references of EP0527914A4 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0514210A3 (en) * 1991-05-15 1993-04-28 The Salk Institute For Biological Studies Grf analogs
US5262519A (en) * 1991-05-15 1993-11-16 The Salk Institute For Biological Studies GRF analogs XI
WO1994011396A1 (fr) * 1992-11-13 1994-05-26 The Administrators Of The Tulane Educational Fund Agonistes de l'hormone de liberation de l'hormone de croissance
WO1994011397A1 (fr) * 1992-11-13 1994-05-26 The Administrators Of The Tulane Educational Fund Agonistes de somatostatine
AU695315B2 (en) * 1993-12-17 1998-08-13 The Administrators Of The Tulane Eductional Fund Analogues of hGH-RH (1-29)NH2 having antagonistic activity
US5550212A (en) * 1993-12-17 1996-08-27 The Administrators Of The Tulane Educational Fund Analogues of hGH-RH(1-29)NH2 having antagonistic activity
WO1995016707A1 (fr) * 1993-12-17 1995-06-22 The Administrators Of The Tulane Educational Fund ANALOGUES DE hGH-RH (1-29)NH2 POSSEDANT UNE ACTIVITE ANTAGONISTE
US6184208B1 (en) 1994-06-29 2001-02-06 Immunotech Developments Inc. Peptide, a method for its preparation and a pharmaceutical composition containing the peptide
US5854216A (en) * 1994-09-23 1998-12-29 Universite De Montreal Marker for growth hormone-releasing factor receptors
US5847066A (en) * 1995-04-14 1998-12-08 The Administrators Of The Tulane Educational Fund Analogs of growth hormone-releasing factor
EP0820296A4 (fr) * 1995-04-14 1999-06-30 Univ Tulane Analogues du facteur liberant l'hormone de croissance
US5942489A (en) * 1996-05-03 1999-08-24 The Administrators Of The Tulane Educational Fund HGH-RH(1-29)NH2 analogues having antagonistic activity
WO2000014236A3 (fr) * 1998-09-08 2000-06-02 Theratechnologies Inc Analogues de somatostatine (grf) à activité biologique accrue
WO2000031136A1 (fr) * 1998-11-25 2000-06-02 Administrators Of The Tulane Educational Fund Analogues antagonistes de gh-rh inhibant igf-i et igf-ii
US6057422A (en) * 1998-11-25 2000-05-02 The Administrators Of The Tulane Educational Fund Antagonistic analogs of GH-RH inhibiting IGF-I and -II
BG65137B1 (bg) * 1998-11-25 2007-03-30 11> Антагонистични аналози на gh-rh инхибиращи igf-i и -ii
CN100422211C (zh) * 1998-11-25 2008-10-01 图兰恩教育基金管理人 抑制igf-i和-ii的gh-rh拮抗性相似物
CN101983068B (zh) * 2008-03-28 2014-12-24 迈阿密大学 N末端和c末端取代的人gh-rh拮抗类似物
US8691942B2 (en) 2008-03-28 2014-04-08 University Of Miami N- and C- terminal substituted antagonistic analogs of GH-RH
WO2009120831A3 (fr) * 2008-03-28 2009-12-23 The University Of Miami Nouveaux analogues antagonistes substitués n- et c-terminaux de gh-rh
US9260504B2 (en) 2008-03-28 2016-02-16 University Of Miami N- and C-terminal substituted antagonistic analogs of GH-RH
EP3473643A1 (fr) 2008-06-12 2019-04-24 Ipsen Bioinnovation Limited Protéines de fusion pour leur utilisation dans le traitement du cancer
EP3590956A1 (fr) 2008-06-12 2020-01-08 Ipsen Bioinnovation Limited Suppression de maladies neuroendocrines
EP2664343A2 (fr) 2008-11-17 2013-11-20 Syntaxin Limited Suppression du cancer
EP3241560A1 (fr) 2008-11-17 2017-11-08 Ipsen Bioinnovation Limited Suppression du cancer
US11993640B2 (en) 2019-02-08 2024-05-28 The United States Government As Represented By The Department Of Veterans Affairs Treating inflammatory lung disease
US12377135B2 (en) 2019-07-18 2025-08-05 University Of Miami GHRH antagonists for use in a method of treating sarcoidosis

Also Published As

Publication number Publication date
JPH06502618A (ja) 1994-03-24
CA2082059A1 (fr) 1991-11-05
EP0527914A4 (en) 1993-08-11
AU7882291A (en) 1991-11-27
EP0527914A1 (fr) 1993-02-24
AU651976B2 (en) 1994-08-11

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