2. Academic Validation
  3. 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

  • Bioorg Med Chem Lett. 2008 Feb 15;18(4):1312-7. doi: 10.1016/j.bmcl.2008.01.027.
Robin D Clark 1,  Nicholas C Ray,  Karen Williams,  Paul Blaney,  Stuart Ward,  Peter H Crackett,  Christopher Hurley,  Hazel J Dyke,  David E Clark,  Peter Lockey,  Rene Devos,  Melanie Wong,  Soraya S Porres,  Colin P Bright,  Robert E Jenkins,  Joseph Belanoff
Affiliations

Affiliation

  • 1 Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA.
PMID: 18226897 DOI: 10.1016/j.bmcl.2008.01.027
Abstract

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin Glucocorticoid Receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

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