解离型非甾体糖皮质激素受体激动剂的鉴定。

Identification of dissociated non-steroidal glucocorticoid receptor agonists.

作者信息

Kuzmich Daniel, Kirrane Tom, Proudfoot John, Bekkali Younes, Zindell Renee, Beck Laura, Nelson Richard, Shih Cheng-Kon, Kukulka Alison J, Paw Zofia, Reilly Patty, Deleon Rodney, Cardozo Mario, Nabozny Gerald, Thomson David

机构信息

Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.

出版信息

Bioorg Med Chem Lett. 2007 Sep 15;17(18):5025-31. doi: 10.1016/j.bmcl.2007.07.031. Epub 2007 Jul 25.

DOI:10.1016/j.bmcl.2007.07.031

PMID:17692519

Abstract

A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.

摘要

描述了一系列新型糖皮质激素受体（GR）配体。通过将3对接至GR活性位点并优化未取代的苯环以实现甾体A环结合口袋中的关键相互作用来指导构效关系（SAR）研究。为了鉴定出副作用比市售甾体有所改善的化合物，在基于细胞的反式激活（芳香化酶）和反式抑制（IL-6）试验中评估了化合物的功能活性。通过这项工作，已鉴定出36在这些基于细胞的试验中为具有解离特征的部分激动剂。