Glucosylceramide synthase inhibitors and therapeutic methods using the same
AssigneeThe Regents of the University of Michigan
InventorsScott D. Larsen, Akira Abe, Liming Shu, Michael William Wilson, Richard F. Keep, Duxin Sun, James A. Shayman
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Abstract
Glucosylceramide synthase inhibitors and compositions containing the same are disclosed. Methods of using the glucosylceramide synthase inhibitors in the treatment of diseases and conditions wherein inhibition of glucosylceramide synthase provides a benefit, like Gaucher disease and Fabry disease, also are disclosed.
Claims24
A compound having a structure
- wherein R1, independently, is selected from the group consisting of halo, C1-3alkyl, C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl, OC1-3alkyl substituted with one to five fluoro atoms, cyclopropyl, CH2cyclopropyl, Ocyclopropyl, and OCH2cyclopropyl;
- NR2R2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one;
- R3 is H, F, or Cl;
- G is (CH2)n;
- m is 1 or 2;
- and
- n is 1 or 2,
- or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(3-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluoro-3-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-yl)acetamide;
- N-((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide;
- 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide;
- N-((1R,2R)-1-(4-(cyclopropylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide;
- and 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.
-11. (canceled)
-14. (canceled)
-25. (canceled)
(canceled)
A compound having a structure
- wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl.
(canceled)
A compound having a structure
- wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl;
- and L is a perfluoroalkylsulfonate or arylsulfonate leaving group.
A compound having a structure
- wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl;
- and NR2R2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one.
-33. (canceled)
A method of treating a disease or condition wherein inhibition of GCS provides a benefit comprising administering a therapeutically effective amount of a compound of claim 32 to an individual in need thereof, wherein the disease or condition is a Gaucher disease, Fabry disease, Sandhoff disease, Tay-Sachs disease, Parkinson's disease, type 2 diabetes, hypertrophy or hyperplasia associated with diabetic neuropathy, an elevated plasma TNF-α level, an elevated blood glucose level, an elevated glycated hemoglobin level, a glomerular disease, or lupus.
(canceled)
A method of inhibiting glucosylceramide synthase or lowering a glycosphinolipid concentration in an individual in need thereof comprising administering a therapeutically effective amount of a compound of claim 32 to the individual.
Dependencies are inferred from the claim text.