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WO2005058322A1 - Utilisation d'antagonistes de recepteur glutamate metabotropique de type 1 (mglur1) pour le traitement de troubles gastro-intestinaux - Google Patents

Utilisation d'antagonistes de recepteur glutamate metabotropique de type 1 (mglur1) pour le traitement de troubles gastro-intestinaux Download PDF

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Publication number
WO2005058322A1
WO2005058322A1 PCT/SE2004/001874 SE2004001874W WO2005058322A1 WO 2005058322 A1 WO2005058322 A1 WO 2005058322A1 SE 2004001874 W SE2004001874 W SE 2004001874W WO 2005058322 A1 WO2005058322 A1 WO 2005058322A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
functional
metabotropic glutamate
glutamate receptor
antagonists
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/SE2004/001874
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English (en)
Inventor
Håkan Larsson
Anders Lehmann
Erik LINDSTRÖM
Jan Mattsson
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.)
AstraZeneca AB
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AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2005058322A1 publication Critical patent/WO2005058322A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • metabotropic glutamate receptor 1 (mGLuRl) antagonists for the treatment of gastrointestinal disorders .
  • the present invention relates to the use of metabotropic glutamate receptor 1 (mGluRl) antagonists for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.
  • mGluRl metabotropic glutamate receptor 1
  • Functional gastrointestinal disorders such as functional dyspepsia
  • mGluR metabotropic glutamate receptors
  • C ⁇ S central nervous system
  • Eight metabotropic glutamate receptor subtypes have been identified and are subdivided into three groups based on sequence similarity, signalling pathways and pharmacology.
  • Group I consists of mGluRl and mGluR5. These receptors activate phospholipase C and increase neuronal excitability.
  • Group II consisting of mGluR2 and mGluR3 as well as group III, consisting of mGluR4, mGluR ⁇ , mGluR7 and mGluRS are capable of inhibiting adenylyl cyclase activity and reduce synaptic transmission.
  • group III consisting of mGluR4, mGluR ⁇ , mGluR7 and mGluRS are capable of inhibiting adenylyl cyclase activity and reduce synaptic transmission.
  • Several of the receptors also exist in various iso forms, occurring by alternative splicing ⁇ Chen, C-Yet al, Journal of Physiology (2002), 538.3, pp. 773-786; Pin, J-P et al, European Journal of Pharmacology (1999), 375, pp. 277-294; Br ⁇ uner-Osborne, Het al. Journal of Medicinal Chemistry (2000), 43, pp.
  • the object of the present invention was to find a new way for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.
  • the present invention relates to the use of metabotropic glutamate receptor 1 (mGluRl) antagonists for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.
  • mGluRl metabotropic glutamate receptor 1
  • the present invention is directed to the use of a metabotropic glutamate receptor 1 antagonist for the manufacture of a medicament for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.
  • Functional dyspepsia refers to pain or discomfort centered in the upper abdomen. Discomfort may be characterized by or combined with upper abdominal fullness, early satiety, bloating or nausea.
  • patients with functional dyspepsia can be divided into two groups: 1- Those with an identifiable pathophysiological or microbiologic abnormality of uncertain clinical relevance (e.g. Helicobacter pylori gastritis, histological duodenitis, gallstones, visceral hypersensitivity, gastroduodenal dysmotility) 2- Patients with no identifiable explanation for the symptoms.
  • Functional dyspepsia can be diagnosed according to the following:
  • Functional dyspepsia can be divided into subsets based on distinctive symptom patterns, such as ulcer-like dyspepsia, dysmotility-like dyspepsia and unspecified (non-specific) dyspepsia.
  • the term "antagonist” should be understood as including full antagonists, inverse agonists, non-competitive antagonists or competitive antagonists, as well as partial antagonists, whereby a “partial antagonist” should be understood as a compound capable of partially, but not fully, in-activating the metabotropic glutamate receptor 1.
  • the present invention is directed to the use of any mGluRl antagonist which has a therapeutic effect in functional gastrointestinal disorders, such as functional dyspepsia.
  • therapeutic effect is defined herein as an effect favourable in the context of the therapy and/or treatment of functional gastrointestinal disorders, such as functional dyspepsia.
  • metabotropic glutamate receptor 1 antagonists are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
  • the metabotropic glutamate receptor 1 antagonists are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
  • the carrier may be in the form of a solid, semi-solid, or liquid diluent.
  • the metabotropic glutamate receptor 1 antagonist(s) to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g.
  • liquid preparations containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol.
  • liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the metabotropic glutamate receptor 1 antagonists may be administered once or twice daily, depending on the severity of the patient's condition.
  • An in vivo gastric distension model is used as a model for functional gastrointestinal disorders, in particular for functional dyspepsia (Bayati A, Astin M, Ekman C, Mattsson H. Wistar Kyoto rats have impaired gastric adaptive accommodation in response to gastric distension. Gastroenterology 2003; 124 (4, suppl 1): W1471 (abstract)).
  • the gastric distension model enables detailed analysis of the physi co-mechanical properties of the stomach, e.g. basal gastric tone, threshold for accommodation, accommodation rate, accommodation volume, and maximal gastric volume.
  • basal gastric tone e.g. basal gastric tone
  • threshold for accommodation
  • accommodation rate accommodation rate
  • accommodation volume e.g. maximal gastric volume.
  • WKY Wistar Kyoto
  • SD Sprague Dawley
  • the advantage of the presently used barostat technique compared to other barostat techniques normally used in experimental clinical studies is that it is possible to discriminate between if a compound exerts its effect directly on gastric smooth muscles or if the effect involves the vagal reflex mechanism.
  • the rats are equipped with fistulas chronically implanted into the stomach.
  • a small inflatable plastic bag with a spherical shape is inserted through fistula into the glandular part of the stomach (middle to distal part in the rat).
  • the experiments are performed in conscious rats.
  • a combination of ramp and tonic distension paradigm is used for detailed analysis of the physico-mechanical properties of the stomach. Pressure and volume data collected during experiments are saved for and further analysis.
  • a balloon is inserted into the stomach of the animal and a four phase protocol which includes a start phase, a ramp phase, a tonic phase and an end phase is performed.
  • the pressure applied to the balloon and the corresponding changes to the volume of the balloon are monitored throughout, e.g., using any barostat system known in the art (e.g., see Toma et al, Neurogastroenterol. Mot, 8, 19-28, 1996).
  • a minimum distension pressure e.g. 1 mmHg
  • a Ramp Phase During this phase the pressure applied to the balloon is increased linearly with a constant increase in pressure.
  • the pressure delivered to the balloon can be between 2-20 mmHg.
  • This phase is then followed by the Tonic Phase.
  • the pressure is kept constant at the maximum pressure.
  • the pressure is dropped to the starting minimum distension pressure and this period is known as the End Phase.
  • the maximum gastric accommodation capacity in the animal following administration of the compound is calculated.
  • a compound of interest will be a compound that alters the maximum gastric accommodation capacity in the animal and this is calculated by determining a difference in the maximum gastric accommodation capacity before and after administration of the compound.
  • the Wistar Kyoto rats (WKY; M&B Denmark) are starved about 8 or 18 hours before each experiment depending on if the experiments are performed in the morning or in the afternoon.
  • a small, inflatable balloon is inserted through the central hole of the fistula into the distal part of stomach under isoflurane anaesthesia (Forene ® , Abbott Scandinavia AB) and fixed in its position through the tightening of the fistula.
  • the balloon has a spherical shape with a wall thickness of about 15 ⁇ m, a non-distensible max diameter of 25 mm and a max volume of about 7 ml.
  • the balloon is connected to a double-lumen polyethylene catheter with an outer diameter of 1.40 mm and a length of about 20 cm.
  • the inner lumen diameter of the catheter was about 0.58 mm.
  • the animals are placed in a specially designed Bollmann cage, with an inner diameter of 60 mm for females and 70 mm for males.
  • the catheter is then, via a pressure transducer, connected to a barostat system.
  • a barostat system maintains the pressure by pumping air into and out of the balloon. After the experiment the balloon and the connecting cable are removed under isoflurane anaesthesia and the animals are returned to their normal cages.
  • a combination of ramp and tonic distension is used in all the experiments.
  • the protocol starts with a minimum distension pressure of 1 mmHg and continues for 20 min in order to collect base line values.
  • the pressure is then increased by a velocity of 1-4 mmHg/min for 10 min to a maximum pressure of 10-20 mmHg (ramp phase).
  • the barostat then keeps the pressure at the maximum pressure for 10 more min (tonic phase).
  • the tonic phase the pressure drops to the minimum distension pressure of 1 mmHg in about Is. The pressure is then kept at this level for another 20-minute period.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention a trait à l'utilisation d'antagonistes de récepteur glutamate métabotropique de type 1 (mGluR1) pour le traitement de troubles gastro-intestinaux, tels que la dyspepsie fonctionnelle.
PCT/SE2004/001874 2003-12-19 2004-12-15 Utilisation d'antagonistes de recepteur glutamate metabotropique de type 1 (mglur1) pour le traitement de troubles gastro-intestinaux Ceased WO2005058322A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0303488-1 2003-12-19
SE0303488A SE0303488D0 (sv) 2003-12-19 2003-12-19 New use 1X

Publications (1)

Publication Number Publication Date
WO2005058322A1 true WO2005058322A1 (fr) 2005-06-30

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PCT/SE2004/001874 Ceased WO2005058322A1 (fr) 2003-12-19 2004-12-15 Utilisation d'antagonistes de recepteur glutamate metabotropique de type 1 (mglur1) pour le traitement de troubles gastro-intestinaux

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SE (1) SE0303488D0 (fr)
WO (1) WO2005058322A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026198A1 (fr) * 1998-11-02 2000-05-11 Eli Lilly And Company Limited Derives d'oxazine (3,6-dihydro)-2h-1,2- n-substitues, leur preparation et leur utilisation comme antagonistes de mglur1 selectifs
WO2001072291A2 (fr) * 2000-03-25 2001-10-04 The Victoria University Of Manchester Traitement de troubles des mouvements
EP1205187A1 (fr) * 1999-08-02 2002-05-15 Yamanouchi Pharmaceutical Co. Ltd. Remedes contre les douleurs neurogenes
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026198A1 (fr) * 1998-11-02 2000-05-11 Eli Lilly And Company Limited Derives d'oxazine (3,6-dihydro)-2h-1,2- n-substitues, leur preparation et leur utilisation comme antagonistes de mglur1 selectifs
EP1205187A1 (fr) * 1999-08-02 2002-05-15 Yamanouchi Pharmaceutical Co. Ltd. Remedes contre les douleurs neurogenes
WO2001072291A2 (fr) * 2000-03-25 2001-10-04 The Victoria University Of Manchester Traitement de troubles des mouvements
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU M.-T. ET AL.: "Agonist- and reflex-evoked internalization of metabotropic glutamate receptor 5 in enteric neurons", JOURNAL OF NEUROSCIENCE, vol. 20, no. 9, 1 May 2000 (2000-05-01), pages 3200 - 3205, XP002986196 *

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