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

被引：46

作者：

Clark, Robin D. ^{[1
]}

Ray, Nicholas C. ^{[2
]}

Williams, Karen ^{[2
]}

Blaney, Paul ^{[2
]}

Ward, Stuart ^{[2
]}

Crackett, Peter H. ^{[2
]}

Hurley, Christopher ^{[2
]}

Dyke, Hazel J. ^{[2
]}

Clark, David E. ^{[2
]}

Lockey, Peter ^{[2
]}

Devos, Rene ^{[2
]}

Wong, Melanie ^{[2
]}

Porres, Soraya S. ^{[2
]}

Bright, Colin P. ^{[2
]}

Jenkins, Robert E. ^{[2
]}

Belanoff, Joseph ^{[1
]}

机构：

[1] Corcept Therapeut, Menlo Pk, CA 94025 USA

[2] Argenta Discovery, Harlow CM19 5TR, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 04期

关键词：

glucocorticoid receptor (GR) antagonist; pyrazolo-fused; azadecalins;

D O I：

10.1016/j.bmcl.2008.01.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1312 / 1317

页数：6

共 17 条

[1] Structural and stereoelectronic requirements for the inhibition of mammalian 2,3-oxidosqualene cyclase by substituted isoquinoline derivatives [J].