Small molecule inhibitors of pendrin ion exchange and pharmaceutical compositions
AssigneeThe Regents of the University of California
InventorsAlan S. Verkman, Peter M. Haggie, Onur Cil
Life of this patent
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Abstract
Provided herein are small molecule inhibitors of pendrin. More specifically, the small molecules disclosed herein may be used to inhibit pendrin-mediated anion exchange. These small molecules may be used for treatment of diseases and disorders that are treatable by inhibiting pendrin, such as cystic fibrosis, rhinitis, chronic rhinosinusitis, exposure to an industrial toxin, certain viral infections, certain bacterial infections, and chronic obstructive pulmonary disease. The small molecules may further be used to potentiate a diuretic effect of a diuretic compound. The small molecules may additionally be used to treat hypertension or thyroid conditions.
Claims19
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound represented by Formula (Ia):
- wherein,
- R1a and R1b are the same or different and independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, trifluoroalkyl, or optionally substituted thioalkyl;
- R3 is hydrogen or halo, provided that when R1b is alkyl, R3 is halo,
- wherein optionally substituted may be unsubstituted or substituted in which at least one hydrogen atom is replaced with a substituent selected from the group consisting of oxo, CO2H, nitrile, nitro, CONH2, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imide, enamine, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, thioalkyl triarylsilyl, perfluoroalkyl, perfluoroalkoxy, —NRgC(═O)NRgRh, —NRgC(═O)ORh, —NRgSO2Rh, —OC(═O)NRgRh, —ORg, —SRg, —SORg, —SO2Rg, —OSO2Rg, —SO2ORg, ═NSO2Rg, —SO2NRgRh, —C(═O)Rg, —C(═O)ORg, —CH2SO2Rg, —CH2SO2NRgRh, —SH, —SRg and —SSRg, wherein Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound represented by Formula (Ib):
- wherein,
- m is 0, 1 or 2;
- R1a and R1b are the same or different and independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, trifluoroalkyl, or optionally substituted thioalkyl;
- and
- each R4 is the same or different and independently halo,
- wherein optionally substituted may be unsubstituted or substituted in which at least one hydrogen atom is replaced with a substituent selected from the group consisting of oxo, CO2H, nitrile, nitro, CONH2, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imide, enamine, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, thioalkyl triarylsilyl, perfluoroalkyl, perfluoroalkoxy, —NRgC(═O)NRgRh, —NRgC(═O)ORh, —NRgSO2Rh, —OC(═O)NRgRh, —ORg, —SRg, —SORg, —SO2Rg, —OSO2Rg, —SO2ORg, ═NSO2Rg, —SO2NRgRh, —C(═O)R, —C(═O)ORg, —CH2SO2Rg, —CH2SO2NRgRh, —SH, —SRg and —SSRg, wherein Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a pyrazolothiophenesulfonamide compound represented by Formula (II):
- wherein,
- R5a and R5b are the same or different and independently hydrogen, or optionally substituted alkyl, provided that R5a and R5b are not both hydrogen;
- R6 and R7 are the same or different and independently hydrogen, optionally substituted alkyl, or —S(O)2NHR, provided one of R6 and R7 is —S(O)2NHR;
- and
- R is optionally substituted aryl or optionally substituted cycloalkyl,
- wherein optionally substituted may be unsubstituted or substituted in which at least one hydrogen atom is replaced with a substituent selected from the group consisting of oxo, CO2H, nitrile, nitro, CONH2, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imide, enamine, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, thioalkyl triarylsilyl, perfluoroalkyl, perfluoroalkoxy, —NRgC(═O)NRgRh, —NRgC(═O)ORh, —NRgSO2Rh, —OC(═O)NRgRh, —ORg, —SRg, —SORg, —SO2Rg, —OSO2Rg, —SO2ORg, ═NSO2Rg, —SO2NRgRh, —C(═O)Rg, —C(═O)ORg, —CH2SO2Rg, —CH2SO2NRgRh, —SH, —SRg and —SSRg, wherein Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
Dependencies are inferred from the claim text.