1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile

Hunt, H. J., Belanoff, J.K., Golding, E., Gourdet, B., Phillips, T., Swift, D., Thomas, J., Unitt, J.F., Walters, I.


We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy.

Ref: Bioorg Med Chem Lett. 2015 Dec 15;25(24):5720-5

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