Small molecule activators of calcium-activated chloride channels and methods of use
View Patent ↗Provided herein are small molecule activators of calcium-activated chloride channels. These small molecules may be used for treatment of diseases and disorders that are treatable by activating calcium-activated chloride channels, such as cystic fibrosis, disorders related to salivary gland dysfunction (for example, Sjogren's syndrome and dysfunction following radiation injury), dry eye syndrome, and intestinal hypomotility.
1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of structure (I):
or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 and R 3 are each independently alkoxy;
R 4 is heteroaralkyl, or heterocyclylalkyl; and
R 5 and R 6 are each independently hydrogen, alkoxy or halo,
wherein the pharmaceutical composition is inhalable and the pharmaceutically acceptable excipient is not dimethyl sulfoxide (DMSO).
2. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures (Ia), (Ib) or (Ic):
3. The pharmaceutical composition of claim 1 , wherein at least one of R 1 , R 2 or R 3 is methoxy.
4. The pharmaceutical composition of claim 1 , wherein R 4 is tetrahydrofuran-2-yl-methyl, furan-2-yl-methyl, tetrahydropyran-2-yl-methyl, pyrid-4-yl-methyl or pyrid-2-yl-methyl.
5. The pharmaceutical composition of claim 1 , wherein at least one of R 5 or R 6 is hydrogen.
6. The pharmaceutical composition of claim 1 , wherein at least one of R 5 or R 6 is methoxy, chloro, or fluoro.
7. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures:
8. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures: