KR20050024351A - Use of MGLUR5 antagonists for the treatment of GERD - Google Patents

Abstract

The present invention relates to the use of metabotropic glutamate receptor 5 antagonists for the inhibition of transient lower esophageal sphincter relaxation. A further aspect of the invention relates to the use of metabotropic glutamate receptor 5 antagonists for the treatment of gastroesophageal reflux disease, as well as for the treatment of reflux and asthma.

Description

Use of MGLUR5 antagonists for the treatment of GERD

The present invention relates to the use of metabotropic glutamate receptor 5 (mGluR5) antagonists for the inhibition of transient hypoesophageal sphincter relaxation. A further aspect of the invention relates to the use of metabotropic glutamate receptor 5 antagonists for the treatment of gastroesophageal reflux disease, as well as for the treatment of reflux.

Metabotropic glutamate receptors (mGluRs) are G protein linked receptors involved in the regulation and activity of many synapses in the central nervous system (CNS). Eight metabotropic glutamate receptor subtypes have been identified and classified into three groups based on sequence similarity. Group I consists of mGluRl and mGluR5. The receptor activates phospholipase C and increases neuronal excitability. In addition to group II consisting of mGluR2 and mGluR3, group III consisting of mGluR4, mGluR6, mGluR7 and mGluR8 can inhibit adenyl cyclase activity and reduce synaptic transmission. Some of these receptors also exist in a variety of isomeric forms, which are caused by alternative splicing (Chen, CY et al., Journal of Physiology (2002), 538.3, pp. 773-786; Pin, JP et al., European Journal of Pharmacology (1999), 375, pp. 277-294; Brauner-Osborne, H et al., Journal of Medicinal Chemistry (2000), 43, pp. 2609-2645; Schoepp, DD, Jane DE Monn JA Neuropharmacology (1999), 38, pp. 1431-1476).

The lower esophageal sphincter (LES) is prone to intermittent relaxation. As a result, gastric juice can lead to the esophagus because the mechanical barrier is temporarily lost at this time, which is hereinafter referred to as "reflux".

Gastroesophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims to reduce gastric acid secretion or neutralize acid in the esophagus. The main mechanism behind reflux is thought to depend on the stockpile esophageal sphincter. However, see, eg, Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535 showed that most reflux events occur during transient lower esophageal sphincter relaxation (TLESRs), that is, relaxation that is not caused by swallowing. In addition, gastric acid secretion has been shown to be normal in patients with GERD.

Blackshaw L.A. Et al., Presentation at the conference Neurogastroenterology & Motility, Madison, Wisconsin, 14 November 2001], metabotropic glutamate receptors of group II and group III, ie mGluR2, mGluR3, mGluR4, mGluR6, mGluR7 and mGluR8, are peripheral mechanical sensory ends. May be involved in the selective inhibition of

It is an object of the present invention to find a novel method for the inhibition of transient lower esophageal sphincter relaxation (TLESRs) and to prevent reflux. More specifically, it is an object of the present invention to find new and improved methods for the treatment of gastroesophageal reflux disease (GERD), as well as new and improved methods for the treatment of reflux.

It has now been surprisingly found that metabotropic glutamate receptor 5 (mGluR5) antagonists are useful for the inhibition of transient lower esophageal sphincter relaxation (TLESRs), and for the treatment of gastroesophageal reflux disease (GERD).

Accordingly, the present invention relates to the use of metabotropic glutamate receptor 5 antagonists for the preparation of drugs for the inhibition of transient lower esophageal sphincter relaxation (TLESRs).

A further aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a drug for preventing reflux.

Still a further aspect of the present invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a medicament for the treatment of gastroesophageal reflux disease (GERD).

Effective prevention of reflux may be an important way of preventing, treating, and treating underdeveloped lung disease due to inhalation of refluxed gastric contents. Thus, a further aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a drug for the treatment of reflux.

Still a further aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a medicament for the treatment or prophylaxis of lung disease.

Another aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a medicament for the treatment of undergrowth.

Still a further aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a medicament for the treatment of asthma, eg reflux associated asthma.

Another aspect of the invention is the use of a metabotropic glutamate receptor 5 antagonist for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.

A further aspect of the invention is a method of inhibiting transient lower esophageal sphincter relaxation (TLESRs), wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Another aspect of the invention is a method of preventing reflux, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Still a further aspect of the present invention is a method of treating gastroesophageal reflux disease (GERD), wherein a pharmaceutically and pharmacologically effective amount of metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Yet another aspect of the present invention is a method of treating reflux, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Still a further aspect of the present invention is a method of treating or preventing asthma, eg reflux associated asthma, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Yet another aspect of the present invention is a method of treating chronic laryngitis, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Still a further aspect of the invention is a method of treating or inhibiting lung disease, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

Still a further aspect of the present invention is a method of treating undergrowth, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist is administered to a subject in need thereof.

For the purposes of the present invention, the term "antagonist" should be understood to include partial antagonists as well as whole antagonists, inverse agonists, noncompetitive antagonists or competitive antagonists, whereby "partial antagonists" refer to metabotropic glutamate receptor 5 It is to be understood as a compound which is partially inactivated but not wholly inactivated.

The word "TLESR", transient hypoesophageal sphincter relaxation, is described herein in Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.

The word "backflow" is defined as gastric juice that can pass up because the mechanical barrier is temporarily lost at this time.

The word “GERD”, GERD [van Heerwarden, M.A., Smout A.J.P.M., 2000; Diagnosis of reflux disease. Bailliere's Clin. Gastroenterol. 14, pp. 759-774.

One example of a compound that has antagonistic affinity for metabotropic glutamate receptor 5 and is useful according to the invention is compound 2-methyl-6- (phenylethynyl) -pyridine (often abbreviated as MPEP). MPEP is commercially available from Tocris, for example, or [K. Sonogashira et al., Tetrahedron Lett. (1975), 50, 4467-4470, can be synthesized according to well known procedures.

Further examples of compounds which have antagonistic affinity for metabotropic glutamate receptor 5 and are useful according to the invention include compounds 3- [3- (5-fluoropyridin-2-yl) -1,2, 4-oxadiazol-5-yl] -5- (methoxymethyl) benzonitrile:

Still another example of a compound having antagonistic affinity for metabotropic glutamate receptor 5 and useful according to the present invention is compound 3-fluoro-5- [3- (5-fluoropyridin-2-yl ) -1,2,4-oxadiazol-5-yl] benzonitrile:

The use of pharmaceutically acceptable salts of metabotropic glutamate receptor 5 antagonists is also within the scope of the present invention. The salt may be, for example, a salt formed with an inorganic acid such as hydrochloric acid; Alkali metal salts such as sodium or potassium salts; Or alkaline earth metal salts such as calcium or magnesium salts.

The metabotropic glutamate receptor 5 antagonist with an asymmetric carbon atom is a chiral compound, and depending on the presence of the asymmetric atom, the metabotropic glutamate receptor 5 antagonist is in the form of a mixture of isomers, especially of pure isomers such as racemates or certain enantiomers. May exist in the form. The use of optical isomers of metabotropic glutamate receptor 5 antagonists is also within the scope of the present invention.

Pharmaceutical Formulations

For clinical use, the metabotropic glutamate receptor 5 antagonist is suitably formulated into a pharmaceutical formulation for oral administration in accordance with the present invention. In addition, rectal, parenteral or any other route of administration may be contemplated by those skilled in the formulation. Thus, the metabotropic glutamate receptor 5 antagonist is formulated with one or more pharmaceutically and pharmacologically acceptable carriers or adjuvants. The carrier may be in the form of a solid, semisolid or liquid diluent.

In the preparation of oral pharmaceutical formulations according to the invention, the metabotropic glutamate receptor 5 antagonist (s) to be formulated is a component of a solid powder, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, Gelatin, or another suitable ingredient, as well as disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. The mixture is then processed into granules or compressed into tablets.

Soft gelatin capsules can be prepared using capsules comprising a mixture of the active compound (s) of the invention, vegetable oils, fats, or other suitable carrier for soft gelatin capsules. Hard gelatine capsules may include components of solid powders such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or active compounds in combination with gelatin.

Dosage units for rectal administration may comprise (i) suppository forms comprising the active substance (s) mixed with a triglyceride base; (ii) a gelatin rectal capsule comprising an active substance mixed with vegetable oil, paraffin oil, or other suitable carrier form for gelatin rectal capsules; (iii) pre-made micro enema forms; Or (iv) in the form of a dry micro enema formulation that is reconstituted in a suitable solvent immediately prior to administration.

Liquid preparations for oral administration are in the form of syrups or suspensions, for example solutions or suspensions, comprising the active compound and the remainder of the formulation consisting of a sugar or sugar alcohol and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol It can be prepared as. If desired, the liquid formulation may include colorants, flavors, saccharin and carboxymethyl cellulose or other thickeners. Liquid formulations for oral administration may also be prepared in the form of dry powder which is reconstituted with a suitable solvent before use.

Solutions for parenteral administration can be prepared as solutions of the compounds of the present invention in pharmaceutically acceptable solvents. The solution may also include stabilizing and / or buffering components and are dispensed in unit doses in the form of ampoules or vials. Solutions for parenteral administration can also be prepared as dry preparations which are immediately reconstituted with a suitable solvent before use.

In one embodiment of the invention, the metabotropic glutamate receptor 5 antagonist may be administered once or twice daily, depending on the severity of the patient's condition.

A typical daily dosage of a metabotropic glutamate receptor 5 antagonist is 0.1-100 mg / kg body weight of the subject to be treated, which depends on various factors such as the route of administration, age and weight of the patient as well as the severity of the patient's condition. Will depend.

Biological assessment

Screening of Compounds Active Against TLESR

A grown Labrador Retriever was trained to participate in the Pavlov sling. Mucosa-to-skin esophageal esophagus was formed in the mucus and the dog was allowed to fully recover before any experiments were performed.

Mobility measurement

Briefly, after approximately 17 hours of fasting with free water supply, a multilumen sleeve / sidehole assembly (Dentsleeve, Adelaide, South Australia) was introduced via esophageal esophageal sphincter, LES) and esophageal pressure were measured. The assembly is perfused with water using a low-compliance liquid pressure pressure perfusion pump (Dentsleeve, Adelaide, South Australia). Swallows were measured by passing the air perfused tube in the oral direction, and the antimony electrode monitored a pH of 3 cm above the LES. All signals were amplified and acquired in a personal computer at 10 Hz.

Once baseline measurements without motor activity on fasting gastric / LES III were obtained, placebo (0.9% NaCl) or test compound was administered intravenously (0.5 ml / kg intravenously) in the forelimb vein. Ten minutes after intravenous administration, nutrients (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) are injected up through the central lumen of the assembly at a final volume of 30 ml / kg at 100 ml / min. Immediately upon this meal, air is blown at 40 ml / min. In an alternative model (Barostat model), nutritional infusion followed by air infusion at a rate of 500 ml / min until an intragastric pressure of 10 ± 1 mmHg was obtained. The pressure is then maintained at this level throughout the experiment using an infusion pump to evacuate the air from further air injection or from above. The experimental time from the start of nutrient infusion to air blowing is 45 minutes. The procedure has been proven as a reliable means of generating TLESRs.

TLESRs are defined as a decrease in the lower esophageal sphincter pressure (for gastric internal pressure) at rates above 1 mmHg / s. Relaxation should not be preceded by a pharyngeal signal of less than 2 s before its commencement, in which case relaxation is defined as swallow-induced. The pressure difference between LES and the stomach should be less than 2 mmHg and the duration of complete relaxation should be longer than 1 s.

Example 1

2-methyl-6- (phenylethynyl) -pyridine (MPEP) was obtained from [K. Sonogashira et al., Tetrahedron Lett. (1975), 50, 4467-4470. After purification by column chromatography (SiO ₂ ), the hydrochloride salt (hydrochloride salt of 2-methyl-6- (phenylethynyl) -pyridine is also commercially available from Tocris, for example) is ice-cold of the product. Prepared by introducing HCl (g) into the Et ₂ O solution. The hydrochloride salt of MPEP was tested in positively grown Labrador Retrievers according to the test model described above.

The number of inhibition of TLESRs was calculated for five previous control experiments for each dog and the results described in Tables 1.1 and 1.2 were achieved.

Standard model compound Dose (μmol / kg) Inhibition% ± SEM (N) MPEP 1.4 30 ± 5 (4) MPEP 4.3 57 ± 8 (4) MPEP 8.7 59 ± 11 (3) N = number of dogs tested SEM = standard error of the mean

Standard model compound Dose (μmol / kg / h) for 60 minutes Inhibition% ± SEM (N) MPEP 4 32 ± 13 (4) MPEP 6 43 ± 3 (2) N = number of dogs tested SEM = standard error of the mean

Example 2

3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] -5- (methoxymethyl) benzonitrile according to the procedure described in WO02 / 068417 Prepared. 3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] -5- (methoxymethyl) benzonitrile was positively synthesized according to the barostat model described above. Tested on grown Labrador Retriever.

Barostat Model compound Dose (μmol / kg / h) for 55 minutes Inhibition% ± SEM (N) 3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] -5- (methoxymethyl) benzonitrile 1.1 58 ± 11 (4) 3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] -5- (methoxymethyl) benzonitrile 2.2 83 ± 17 (2) N = number of dogs tested SEM = standard error of the mean

Example 3

3-Fluoro-5- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] benzonitrile was prepared according to the procedure described in WO01 / 12627. Positively grown Labrador Retriever with 3-fluoro-5- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] benzonitrile according to the barostat model described above Tested at

Barostat Model compound Dose (μmol / kg / h) for 60 minutes Inhibition% ± SEM (N) 3-fluoro-5- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] benzonitrile One 70 ± 4 (3) N = number of dogs tested SEM = standard error of the mean

The results shown in the above examples support that metabotropic glutamate receptor 5 antagonists are useful for the inhibition of TLESRs and therefore useful for the treatment of GERD.

Claims (28)

Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof for the manufacture of a drug for the inhibition of transient lower esophageal sphincter relaxation (TLESRs). Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof for the manufacture of a medicament for the treatment of gastroesophageal reflux disease (GERD). Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof for the manufacture of a medicament for the prevention of reflux. Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof for the manufacture of a medicament for the treatment of, or prevention of regurgitation. Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof for the manufacture of a medicament for the treatment or prevention of asthma. 6. Use according to claim 5, wherein the asthma is reflux related asthma. Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof for the manufacture of a medicament for the treatment or prevention of chronic laryngitis. Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof for the manufacture of a medicament for the treatment or prophylaxis of lung disease. Use of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof for the manufacture of a medicament for the treatment of underdeveloped. 10. Use according to any one of the preceding claims, characterized in that the metabotropic glutamate receptor 5 antagonist is 2-methyl-6- (phenylethynyl) -pyridine. Use according to claim 10, characterized in that the metabotropic glutamate receptor 5 antagonist is a hydrochloride salt of 2-methyl-6- (phenylethynyl) -pyridine. The method of claim 1, wherein the metabotropic glutamate receptor 5 antagonist is 3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazole- 5-yl] -5- (methoxymethyl) benzonitrile. The method of claim 1, wherein the metabotropic glutamate receptor 5 antagonist is 3-fluoro-5- [3- (5-fluoropyridin-2-yl) -1,2,4 -Oxadiazol-5-yl] benzonitrile. Use according to any one of claims 1 to 13, characterized in that the daily dose of the metabotropic glutamate receptor 5 antagonist is 0.1-100 mg / kg body weight of the subject to be treated. A method of inhibiting transient lower esophageal sphincter relaxation (TLESRs), wherein a pharmaceutically and pharmacologically effective amount of metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or optical isomer thereof is administered to a subject in need thereof. A method of treating gastroesophageal reflux disease (GERD), wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof is administered to a subject in need thereof. A method of preventing reflux, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof is administered to a subject in need thereof. A method of treating or preventing regurgitation, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof is administered to a subject in need of treatment or prevention. A method of preventing or treating lung disease, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof is administered to a subject in need of treatment or prevention. A pharmaceutical and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof, is administered to a subject in need thereof. A method of treating or preventing asthma, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof or an optical isomer thereof is administered to a subject in need of treatment or prevention. 22. The method of claim 21, wherein said asthma is reflux related asthma. A method of treating or preventing chronic laryngitis, wherein a pharmaceutically and pharmacologically effective amount of a metabotropic glutamate receptor 5 antagonist, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof is administered to a subject in need of treatment or prevention. 24. The method of any one of claims 15 to 23, wherein the metabotropic glutamate receptor 5 antagonist is 2-methyl-6- (phenylethynyl) -pyridine. 25. The method of claim 24, wherein the metabotropic glutamate receptor 5 antagonist is a hydrochloride salt of 2-methyl-6- (phenylethynyl) -pyridine. The method of claim 15, wherein the metabotropic glutamate receptor 5 antagonist is 3- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazole- 5-yl] -5- (methoxymethyl) benzonitrile. 24. The method of any one of claims 15 to 23, wherein the metabotropic glutamate receptor 5 antagonist is 3-fluoro-5- [3- (5-fluoropyridin-2-yl) -1,2,4 -Oxadiazol-5-yl] benzonitrile. 28. The method of any one of claims 15 to 27, wherein the daily dose of the metabotropic glutamate receptor 5 antagonist is 0.1-100 mg / kg body weight of the subject to be treated.