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

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 Ki 0.7 nM; GR reporter gene functional Ki 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

Graphical abstractFusion of the 4-fluorophenylpyrazole group onto the azadecalin system afforded high affinity glucocorticoid receptor (GR) antagonists. The bridgehead position was tolerant to substitution and larger groups afforded optimal GR antagonist functional activity, e.g., methoxyethyl ether 52 had a hGR binding Ki of 0.7 nM and a hGR functional antagonist Ki of 0.6 nM in a reporter gene assay.Figure optionsDownload full-size imageDownload as PowerPoint slide