Methods of Treating Psychiatric or Neurological Disorders with MGLUR Antagonists

• US 20130225623A1
• Filed: 10/27/2010
• Published: 08/29/2013
• Est. Priority Date: 10/27/2010
• Status: Abandoned Application

• Current Assignee: Mount Sinai School of Medicine (Sinai Health System)
• Original Assignee: Mount Sinai School of Medicine (Sinai Health System)
• Inventors: Buxbaum, Joseph, Sakurai, Takeshi, (Bozdagi) Gunal, Ozlem
• Application Number:
  US13/504,847
• Publication Number:
  US 20130225623A1
• Time in Patent Office: Days
• US Class Current: 514/277
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Methods for treating a psychiatric or neurological disease or disorder using combinations of Group 1 mGluR antagonists are disclosed. In certain aspects, these methods include the treatment of a patient having a neurological or psychiatric disease or disorder associated with a CYFIP1 gene change.

Claims

1. A method for treating a patient having a disease or disorder associated with a CYFIP1 gene change, which comprises the steps of:

identifying a patient in need of such treatment and administering to said patient an effective amount for treating said disease or disorder of a composition comprising an mGluR5 antagonist and an mGluR1 antagonist.

2. The method of claim 1, wherein the disease or disorder is selected from the group consisting of an autism spectrum diagnosis (ASD), Fragile X syndrome, schizophrenia, Prader-Willi syndrome, and Angelman syndrome.

3. The method of claim 1, wherein the mGluR1 antagonist is a member selected from the group consisting of:

LY367385, A 841720, LY 456236 hydrochloride, Bay 36-7620 and CPCCOEt.

4. The method of claim 1, wherein the mGluR5 antagonist is a member selected from the group consisting of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), (E)-6-methyl-2-styryl-pyridine (SIB 1893), LY293558, 2-methyl-6-[(1E)-2-phenylethynyl]-pyridine, 6-methyl-2-(phenylazo)-3-pyridinol, (RS)-α

-methyl-4-carboxyphenylglycine (MCPG), 3S,4aR,6S,8aRS-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3S,4aR,6S,8aR-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3SR,4aRS,6SR,8aRS-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, [N-(3-chlorophenyl)-N′

-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea](Fenobam), 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP hydrochloride), and 3S,4aR,6S,8aR-6-(((4-carboxy)-phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.

5. The method of claim 1, wherein the patient is a human.

6. The method of claim 1, which comprises administering the mGluR5 antagonist in a dose ranging from between about 0.0001 mg to about 100 mg per kilogram of body weight per day.

7. The method of claim 1, which comprises administering the mGluR1 antagonist in a dose ranging from between about 0.0001 mg to about 100 mg per kilogram of body weight per day.

8. The method of claim 1, wherein the CYFIP1 gene change is a member selected from the group consisting of a CYFIP1 duplication, a CYFIP1 deletion, a mutation in the CYFIP1 gene resulting in increased expression of CYFIP1, and a mutation in the CYFIP1 gene resulting in decreased expression of CYFIP1.

17. The method of claim 1, which comprises intravenously administering the composition.

29. The method of claim 1, wherein the mGlur5 antagonist is 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the mGluR1 antagonist is LY367385.

9. A method for treating a neurological or psychiatric disease or disorder, which comprises administering to a patient in need of such treatment an effective amount for treating said disease or disorder of a composition comprising an mGluR5 antagonist and an mGluR1 antagonist.

10. The method of claim 9, wherein the disease or disorder is a member selected from the group consisting of an autism spectrum diagnosis (ASD), Fragile X syndrome, schizophrenia, Prader-Willi syndrome, and Angelman syndrome.

11. The method of claim 9, wherein the mGluR1 antagonist is a member selected from the group consisting of LY367385, A 841720, LY 456236 hydrochloride, Bay 36-7620 and CPCCOEt.

12. The method of claim 9, wherein the mGluR5 antagonist is a member selected from the group consisting of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), (E)-6-methyl-2-styryl-pyridine (SIB 1893), LY293558, 2-methyl-6-[(1E)-2-phenylethynyl]-pyridine, 6-methyl-2-(phenylazo)-3-pyridinol, (RS)-α

-methyl-4-carboxyphenylglycine (MCPG), 3S,4aR,6S,8aRS-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3S,4aR,6S,8aR-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3SR,4aRS,6SR,8aRS-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, [N-(3-chlorophenyl)-N′

-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] (Fenobam), 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP hydrochloride), and 3S,4aR,6S,8aR-6-(((4-carboxy)-phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.

13. The method of claim 9, wherein the patient is a human.

14. The method of claim 9, which comprises administering the mGluR5 antagonist in a dose ranging from between about 0.0001 mg to about 100 mg per kilogram of body weight per day.

15. The method of claim 9, which comprises administering the mGluR1 antagonist in a dose ranging from between about 0.0001 mg to about 100 mg per kilogram of body weight per day.

18. The method of claim 9, which comprises intravenously administering the composition.

22. The method of claim 9, wherein said neurological or psychiatric disease or disorder is associated with a copy number variation in the 15q11.2 gene region.

30. The method of claim 9, wherein the mGlur5 antagonist is 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the mGluR1 antagonist is LY367385.

16. A pharmaceutical composition comprising (a) an mGluR5 antagonist and an mGluR1 antagonist in an effective amount for treating a disease or disorder associated with a CYFIP1 gene change;

and (b) a pharmaceutically acceptable carrier or diluent.

19. The pharmaceutical composition of claim 16, wherein the disease or disorder is a member selected from the group consisting of an autism spectrum diagnosis (ASD), Fragile X syndrome, schizophrenia, Prader-Willi syndrome, and Angelman syndrome.

20. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 16.

21. The pharmaceutical dosage form of claim 20 which is a tablet or capsule.

23. A pharmaceutical composition comprising (a) an mGluR5 antagonist and an mGluR1 antagonist in an effective amount for treating a disease or disorder associated with a copy number variation (CNV) in the 15q11.2 gene region;

and (b) a pharmaceutically acceptable carrier or diluent.

24. The pharmaceutical composition of claim 23, wherein the disease or disorder is a member selected from the group consisting of an autism spectrum diagnosis (ASD), Fragile X syndrome, schizophrenia, Prader-Willi syndrome, and Angelman syndrome.

25. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 23.

26. The pharmaceutical dosage form of claim 25 which is a tablet or capsule.

31. The pharmaceutical composition of claim 23, wherein the mGlur5 antagonist is 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the mGluR1 antagonist is LY367385.

27. A method for treating a patient having a disease or disorder associated with a copy number variation (CNV) in the 15q11.2 gene region, which comprises the steps of:

identifying a patient in need of such treatment and administering to said patient an effective amount for treating said disease or disorder of a composition comprising an mGluR5 antagonist in combination with an mGluR1 antagonist.

28. The method of claim 27, wherein the mGlur5 antagonist is 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the mGluR1 antagonist is LY367385.