Methods for treating glaucoma and macular degeneration
Inhibition of geranylgeranylation of Rho GTPases and heterotrimeric G-proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through the tissue relaxation, and through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. In addition, such inhibition is useful for treating age-related macular degeneration. The GGTase-I enzyme is a molecular target for lowering increased ocular pressure in glaucoma patients.
1. A method of treating glaucoma in a patient, comprising:
administering a selective inhibitor of geranylgeranyl transferase I (GGTI) to the patient, wherein the inhibitor competes with substrate protein for the CaaX peptide binding site on the GGTI, wherein the inhibitor inhibits geranylgeranyl transferase I at least 5 times more potently than farnesyl transferase, thereby increasing aqueous humor outflow through the trabecular meshwork pathway.
2. The method of claim 1 wherein the inhibitor of geranylgeranyl transferase is a cyclic acid anhydride comprising a lipid chain.
3. The method of claim 1 wherein the inhibitor is administered orally.
4. The method of claim 1 wherein the inhibitor is administered topically.
5. The method of claim 1 wherein the inhibitor is GGTI-286 having a structure
wherein R═OCH 3 , or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the inhibitor is GGTI-287 having a structure
wherein R═O − , or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 wherein the inhibitor is GGTI-297 having a structure
wherein R═H, or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 wherein the inhibitor is GGTI-298 having a structure
wherein R═CH 3 , or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 wherein the inhibitor is GGTI-2133 having a structure
wherein R═H, and Ar=1-naphthyl, or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 wherein the inhibitor is GGTI-2147 having a structure
wherein R═CH 3 , and Ar=1-naphthyl, or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 wherein the inhibitor is GGTI-2166 having a structure
wherein R═CH 3 , or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 wherein the inhibitor is a compound of the following formula:
wherein Ar is
each X is independently C, N, O or S;
R 1 is phenyl, benzyl, methyl, ethyl, propyl, pyrimidine, 3,4-dimethylphenyl, 3-chloropyridazine, 2,4-dimethylpyrimidine, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, CH 2 CF 3 , 4-trifluoromethylphenyl, 4-nitrophenyl, 4-bromophenyl, 3-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chloro-2-methylphenyl, 4-fluorophenyl, 4-sulfonamidophenyl, 3-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 3,5-difluorophenyl, 4-aminophenyl, 1,3-dimethylpyrazole, ethanol, or 3,4-methylenedioxyphenyl;
R 2 is methyl, pyridine, pyridine-1-oxide, 3-cyanophenyl, 3-aminophenyl, 3-amidinophenyl, 3-dimethylaminophenyl, 2-methylthiazole, 4-methylthiadiazole, thiadiazole, 5-methylisoxazole, pyrazine, pyrimidine, 5-methylimidazole, 5-methylpyrazole, 2-benzylsulfanylpyridine, 6-benzylsulfanylpyridine, CH 2 COOH, N(CH 3 ) 2 , CH 2 CH 2 SCH 3 or CH 2 -piperidinyl;
R 3 is absent, H, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 NHCH 3 , CH 2 OH, (CH 2 ) 3 OH, CH 2 CH 2 CO 2 H, CH 2 CO 2 H, CH 2 CH 2 SOCH 3 , CH 2 CH 2 SO 2 CH— 3 , CH 2 CH 2 SH or CH 2 CH 2 SCH 3 ;
R 4 is absent, H, NH 2 , CON(CH 3 ) 2 , CO 2 H, CN, CH 2 OH, CONH 2 , CSNH 2 , CONHOH, C(NH)NH 2 , CONHNH 2 , CONHCH 3 , CH 2 OCH 3 , CONH-cyclohexyl, CO 2 CH 3 ,
R 5 is absent, isopropyl, benzyl, 4-trifluoromethylbenzyl, 4-cyanobenzyl, 4-benzoylbenzyl, 3-chlorobenzyl, pentafluorobenzyl, 3,4-dichlorobenzyl, 2-fluorobenzyl, 4-methoxybenzyl, CH 2 CH 2 -phenyl, 4-fluorobenzyl, 4-phenylbenzyl, CH 2 -imidazole, CH 2 COOH, CH 2 CH 2 COOH, (CH 2 ) 4 NH 2 , CH 2 CH 2 SCH 3 , 4-hydroxybenzyl, CH 2 -naphthyl, 4-methylbenzyl, CH 2 -indole, CH 2 -thiophene, CH 2 -cyclohexane, 4-chlorobenzyl, phenyl, 2 -hydroxybenzyl, 4-tertbutoxybenzyl, CH 2 -benzylimidazole, 4-aminobenzyl, CH 2 -pryid-3-yl, CH 2 -pryid-2-yl, CH 2 OH, (CH 2 ) 3 NHC(NH)NH 2 or CH 2 CH(CH 3 ) 2 ; and,
R 6 is H, methyl, ethyl, propyl, isopropyl, CH 2 CO 2 H, CH 2 CO 2 Et, benzyl, or CH 2 -(2-methoxynaphthyl); or,
R 5 and R 6 together form:
13. The method of claim 1 wherein the inhibitor is GGTI-396586 (GGTI-DU40; N—[(S)-1-Carbamoyl-2-pheylethyl]-4-[2-(3,4-diclolorophenyl)-4-(2-methylsulfanylethyl)-5-pyridin-3-yl-2-H-pyrazol-3-yloxy]butyramide) or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 250 times more potently than farnesyl transferase.
15. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 10 times more potently than farnesyl transferase.
16. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 20 times more potently than farnesyl transferase.
17. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 25 times more potently than farnesyl transferase.
18. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 35 times more potently than farnesyl transferase.
19. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 45 times more potently than farnesyl transferase.
20. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I at least 50 times more potently than farnesyl transferase.
21. The method of claim 1 wherein adenosine triphosphate is administered with or prior to the inhibitor.
22. The method of claim 1 wherein the inhibitor inhibits geranylgeranyl transferase I with a K i <1 nM.
23. The method of claim 1 wherein the inhibitor is GGTI-DU40 (N—[(S)-1-Carbamoyl-2-phenylethyl]-4-[2-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-5-pyridin-3-yl-2-H-pyrazol-3-yloxy]butyramide, FW=612.58).
24. The method of claim 3 wherein the inhibitor is GGTI-DU40 (N—[(S)-1-Carbamoyl-2-phenylethyl]-4-[2-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-5-pyridin-3-yl-2-H-pyrazol-3-yloxy]butyramide, FW=612.58).
25. The method of claim 4 wherein the inhibitor is GGTI-DU40 (N—[(S)-1-Carbamoyl-2-phenylethyl]-4-[2-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-5-pyridin-3-yl-2-H-pyrazol-3-yloxy]butyramide, FW=612.58).
26. The method of claim 21 wherein the inhibitor is GGTI-DU40 (N—[(S)-1-Carbamoyl-2-phenylethyl]-4-[2-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-5-pyridin-3-yl-2-H-pyrazol-3-yloxy]butyramide, FW=612.58).