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

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

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.

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