Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

Abstract

The use of inhibitors of GSK-3 useful for treating glaucoma is disclosed.

1 - 4 . (canceled) 
     
     
         5 . A method for treating glaucomatous optic neuropathy comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising at least one glycogen synthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptable carrier, wherein said GSK-3 inhibitor is a compound selected from the group consisting of indirubine analogs, 2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivatives or analogs, hymenialdesine or derivatives or analogs thereof, and paullone analogs. 
     
     
         6 . The method of  claim 5 , wherein the GSK-3 inhibitor is an indirubine analog. 
     
     
         7 . The method of  claim 6 , wherein the indrubine analog is selected from the group consisting of indirubine, 5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide) indirubine, indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamide indirubine. 
     
     
         8 . The method of  claim 5 , wherein the GSK-3 inhibitor is a 2,4-diaminothiazole analog. 
     
     
         9 . The method of  claim 8 , wherein the 2,4-diaminothiazole analog is selected from the group consisting of: 
       (4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone, 
       (4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)phenylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone, 
       4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone, 
       (4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)ethanone, 
       [4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone, 
       [4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone, 
       [4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone, 
       3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethyl ester 
       [4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, and 
       (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone. 
     
     
         10 . The method of  claim 5 , wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylic acid derivative or analog. 
     
     
         11 . The method of  claim 10 , wherein the 1,2,4-triazole-carboxylic acid derivative or analog is selected from the group consisting of: 
       3-amino-5-anilino-2-benzoyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide, 
       3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide, 
       3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole, 3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole, 
       3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-phenoxyphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-bromo-2-methylphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (3-methoxyphenyl)amide, 
       3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid (4-chlorophenyl)amide, and 
       3,5-diamino2-benzoyl-1,2,4-triazole. 
     
     
         12 . The method of  claim 5 , wherein the GSK-3 inhibitor is a hymenialdisine derivative or analog. 
     
     
         13 . The method of  claim 12 , wherein the hymenialdesine derivative or analog is selected from the group consisting of: 
       Hymenialdisine (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5 ,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one), 
       4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one, and 
       (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one. 
     
     
         14 . The method of  claim 5 , wherein the GKS-3 inhibitor is a paullone analog. 
     
     
         15 . The method of  claim 14 , wherein the paullone analog is selected from the group consisting of 9-nitropaullone, 9-bromopaullone, 9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in the methods of the invention. 
     
     
         16 . The method of claim  1 , wherein said administering is topical application, intracamerally or via an implant. 
     
     
         17 . The method of claim  1 , wherein the concentration of said GSK-3 inhibitor in said composition is from 0.01% to 2%. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A method for lowering intraocular pressure (IOP) in a patient in need thereof comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising at least one glycogen synthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptable carrier, wherein said GSK-3 inhibitor is a compound selected from the group consisting of indirubine analogs, 2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivatives or analogs, hymenialdesine or derivatives or analogs thereof, and paullone analogs. 
     
     
         23 . The method of  claim 22 , wherein the GSK-3 inhibitor is an indirubine analog. 
     
     
         24 . The method of  claim 23 , wherein the indrubine analog is selected from the group consisting of indirubine, 5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide) indirubine, indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamide indirubine. 
     
     
         25 . The method of  claim 22 , wherein the GSK-3 inhibitor is a 2,4-diaminothiazole analog. 
     
     
         26 . The method of  claim 25 , wherein the 2,4-diaminothiazole analog is selected from the group consisting of: 
       (4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone, 
       (4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)phenylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone, 
       4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone, 
       (4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)ethanone, 
       [4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone, 
       [4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone, 
       [4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone, 
       3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethyl ester 
       [4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, and 
       (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone. 
     
     
         27 . The method of  claim 22 , wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylic acid derivative or analog. 
     
     
         28 . The method of  claim 27 , wherein the 1,2,4-triazole-carboxylic acid derivative or analog is selected from the group consisting of: 
       3-amino-5-anilino-2-benzoyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide, 
       3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide, 
       3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2((3-benzoyl)benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole, 
       3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-phenoxyphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-bromo-2-methylphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (3-methoxyphenyl)amide, 
       3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid (4-chlorophenyl)amide, and 
       3,5-diamino2-benzoyl-1,2,4-triazole. 
     
     
         29 . The method of  claim 22 , wherein the GSK-3 inhibitor is a hymenialdisine derivative or analog. 
     
     
         30 . The method of  claim 29 , wherein the hymenialdesine derivative or analog is selected from the group consisting of: 
       Hymenialdisine (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one), 
       4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one, and 
       (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one. 
     
     
         31 . The method of  claim 22 , wherein the GKS-3 inhibitor is a paullone analog. 
     
     
         32 . The method of  claim 31 , wherein the paullone analog is selected from the group consisting of 9-nitropaullone, 9-bromopaullone, 9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in the methods of the invention. 
     
     
         33 . The method of  claim 18 , wherein said administering is topical application, intracamerally or via an implant. 
     
     
         34 . The method of  claim 18 , wherein the concentration of said GSK-3 inhibitor in said composition is from 0.01% to 2%. 
     
     
         35 . The method of  claim 18 , wherein said patient suffers from glaucoma or ocular hypertension. 
     
     
         36 . The method of  claim 35 , wherein said glaucoma is normal-tension glaucoma. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . A method for preventing or inhibiting glaucomatous optic neuropathy and controlling IOP in a patient in need thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising at least one glycogen synthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptable carrier, wherein said GSK-3 inhibitor is a compound selected from the group consisting of indirubine analogs, 2,4-diaminothiazole analogs, 1,2,4-triazole-carboxylic acid derivatives or analogs, hymenialdesine or derivatives or analogs thereof, and paullone analogs. 
     
     
         42 . The method of  claim 41 , wherein the GSK-3 inhibitor is an indirubine analog. 
     
     
         43 . The method of  claim 42 , wherein the indrubine analog is selected from the group consisting of indirubine, 5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide) indirubine, indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamide indirubine. 
     
     
         44 . The method of  claim 41 , wherein the GSK-3 inhibitor is a 2,4-diaminothiazole analog. 
     
     
         45 . The method of  claim 44 , wherein the 2,4-diaminothiazole analog is selected from the group consisting of: 
       (4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone, 
       (4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)phenylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone, 
       (4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone, 
       4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone, 
       (4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone, 
       (4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone, 
       1-(4-amino-2-phenylaminothiazol-5-yl)ethanone, 
       [4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone, 
       [4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone, 
       [4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone, 
       3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethyl ester 
       [4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, 
       [4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone, and 
       (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone. 
     
     
         46 . The method of  claim 41 , wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylic acid derivative or analog. 
     
     
         47 . The method of  claim 46 , wherein the 1,2,4-triazole-carboxylic acid derivative or analog is selected from the group consisting of: 
       3-amino-5-anilino-2-benzoyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide, 
       3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide, 
       3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole, 
       3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole, 
       3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-phenoxyphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (4-bromo-2-methylphenyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide, 
       3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (3-methoxyphenyl)amide, 
       3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid (4-chlorophenyl)amide, and 
       3,5-diamino2-benzoyl-1,2,4-triazole. 
     
     
         48 . The method of  claim 41 , wherein the GSK-3 inhibitor is a hymenialdisine derivative or analog. 
     
     
         49 . The method of  claim 48 , wherein the hymenialdesine derivative or analog is selected from the group consisting of: 
       Hymenialdisine (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one), 
       4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one, and 
       (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one. 
     
     
         50 . The method of  claim 41 , wherein the GKS-3 inhibitor is a paullone analog. 
     
     
         51 . The method of  claim 50 , wherein the paullone analog is selected from the group consisting of 9-nitropaullone, 9-bromopaullone, 9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in the methods of the invention. 
     
     
         52 . The method of  claim 37 , wherein said administering is topical application, intracamerally or via an implant. 
     
     
         53 . The method of  claim 37 , wherein the concentration of said GSK-3 inhibitor in said composition is from 0.01% to 2%. 
     
     
         54 . The method of  claim 37 , wherein said patient suffers from glaucoma or ocular hypertension. 
     
     
         55 . The method of  claim 54 , wherein said glaucoma is normal-tension glaucoma.