Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 2: Synthesis and inhibitory activity of aryl-3-trifluoromethylpyrazoles

To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure–activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.

4′-Chloro-5-(substituted-pyrazolyl)thiophene-2-carboxanilide (1), 1-methyl-5-substituted-3-trifluoromethyl-1H-pyrazole (2) and 4′-[3,5-bis(trifluoromethyl)pyrazol-1-yl]carboxanilide (3) derivatives were prepared and evaluated for their CRAC channel inhibitory activity.Figure optionsDownload as PowerPoint slide