WO2005058322A1

WO2005058322A1 - USE OF METABOTROPIC GLUTAMATE RECEPTOR 1 (mGLuR1) ANTAGONISTS FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS

Info

Publication number: WO2005058322A1
Application number: PCT/SE2004/001874
Authority: WO
Inventors: Håkan Larsson; Anders Lehmann; Erik LINDSTRÖM; Jan Mattsson
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-12-19
Filing date: 2004-12-15
Publication date: 2005-06-30
Anticipated expiration: 2006-06-19
Also published as: SE0303488D0

Abstract

The present invention relates to the use of metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.

Description

Use of metabotropic glutamate receptor 1 (mGLuRl) antagonists for the treatment of gastrointestinal disorders .

Field of the invention 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.

Background of the invention

Functional gastrointestinal disorders, such as functional dyspepsia, can be defined in accordance with Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, Talley NJ, Thompson WG, Whitehead WE, Coraziarri E, eds. Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, NA: Degnon Associates, Inc.; 2000:351-432 and Drossman DA, Corazziari E, Talley ΝJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45(Suppl.2), II1-II81.9-1-1999. The metabotropic glutamate receptors (mGluR) are G-protein coupled receptors that are involved in the regulation and activity of many synapses in the central nervous system (CΝS). 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, mGluRό, 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; Brάuner-Osborne, Het al. Journal of Medicinal Chemistry (2000), 43, pp. 2609-2645; Schoepp, D.D, Jane D.E. Monn J.A. Neuropharmacology (1999), 38, pp. 1431-1476). The object of the present invention was to find a new way for the treatment of functional gastrointestinal disorders, such as functional dyspepsia.

Outline of the invention

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.

Consequently, 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. Etiologically, 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:

At least 12 weeks, which need not be consecutive within the preceding 12 months of 1- Persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen) and 2- No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms and 3- No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or form.

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.

Currently existing therapy of functional dyspepsia is largely empirical and directed towards relief of prominent symptoms. The most commonly used therapies, still include antidepressants.

For the purpose of this invention, 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.

The term "therapy" and/or "treatment" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

The term "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. Pharmaceutical formulations

For clinical use, the 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. Thus, 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.

In the preparation of oral pharmaceutical formulations in accordance with the invention, 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. The mixture is then processed into granules or compressed into tablets.

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. solutions or suspensions, 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. If desired, such 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.

In one aspect of the present invention, the metabotropic glutamate receptor 1 antagonists may be administered once or twice daily, depending on the severity of the patient's condition.

Biological evaluation

Methods

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. By using the same model in both rats and humans it has been found that the gastric volume responses is very similar in the rat glandular stomach to that in human proximal stomach. Furthermore, it has been shown that patients with Functional Dyspepsia as well as Wistar Kyoto (WKY) rats have an impaired gastric adaptive response and also a lower total gastric volume as compared to healthy subjects and Sprague Dawley (SD) rats, respectively. In addition, the method has shown to be reproducible and reliable. Moreover, 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. During gastric experiments, 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. For detailed analysis of the physico-mechanical properties of the stomach, a combination of ramp and tonic distension paradigm is used. Pressure and volume data collected during experiments are saved for and further analysis.

In order to determine an animal's maximum gastric accommodation capacity, 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).

During the start phase a minimum distension pressure, e.g., 1 mmHg, is applied to the balloon until base line values are obtained. This is followed by 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. During the tonic phase the pressure is kept constant at the maximum pressure. Finally the pressure is dropped to the starting minimum distension pressure and this period is known as the End Phase.

To determine if an agent, e.g., a compound is useful in the treatment of FD, 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 μm, 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). After 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.

Claims

1. Use of a metabotropic glutamate receptor 1 antagonist, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of a functional gastrointestional disorder.

2. Use according to claim 1, wherein the functional gastrointestinal disorder is functional dyspepsia.

3. A method for the treatment of a functional gastrointestinal disorder whereby a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 1 antagonist, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment.

4. The method according to claim 3, wherein the functional gastrointestinal disorder is functional dyspepsia.