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

@article{Hunt20151HPyrazolo34ghexahydroisoquinolinesAP,
  title={1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile.},
  author={Hazel J Hunt and Joseph K. Belanoff and Emily Golding and Beno{\^i}t Gourdet and Timothy Packard Phillips and Denise Swift and Jennifer C. Thomas and John F. Unitt and Iain Loughborough Walters},
  journal={Bioorganic & medicinal chemistry letters},
  year={2015},
  volume={25 24},
  pages={
          5720-5
        }
}
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. 
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