1H-Pyrazolo[3, 4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile. Issue 24 (15th December 2015)

• Record Type: Journal Article
• Authors: Hunt, Hazel J.; Belanoff, Joseph K.; Golding, Emily; Gourdet, Benoit; Phillips, Timothy; Swift, Denise; Thomas, Jennifer; Unitt, John F.; Walters, Iain
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 24(2015)
• Page Start: 5720
• Page End: 5725
• Publication Date: 2015-12-15
• Subjects: Glucocorticoid receptor antagonists -- 1H-Pyrazolo[3, 4-g]hexahydro-isoquinolines -- Insulin resistance -- hERG inhibition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.097
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We report the further optimization of our series 1 H -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.