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

  • Bioorg Med Chem Lett. 2015 Dec 15;25(24):5720-5. doi: 10.1016/j.bmcl.2015.10.097.
Hazel J Hunt  1 ,  Joseph K Belanoff  2 ,  Emily Golding  3 ,  Benoit Gourdet  3 ,  Timothy Phillips  3 ,  Denise Swift  3 ,  Jennifer Thomas  3 ,  John F Unitt  3 ,  Iain Walters  3
Affiliations
  • 1. Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, USA. Electronic address: [email protected].
  • 2. Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, USA.
  • 3. Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
PMID: 26546213 DOI: 10.1016/j.bmcl.2015.10.097
Abstract

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.

Keywords
1H-Pyrazolo[3,4-g]hexahydro-isoquinolines; Glucocorticoid receptor antagonists; Insulin resistance; hERG inhibition.