三环咪唑并[4,5-b]吡啶-2-酮作为促肾上腺皮质激素释放因子-1拮抗剂的设计与合成

Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.

作者信息

Guo Zhiqiang, Tellew John E, Gross Raymond S, Dyck Brian, Grey Jonathan, Haddach Mustapha, Kiankarimi Mehrak, Lanier Marion, Li Bin-Feng, Luo Zhiyong, McCarthy James R, Moorjani Manisha, Saunders John, Sullivan Robert, Zhang Xiaohu, Zamani-Kord Said, Grigoriadis Dimitri E, Crowe Paul D, Chen Ta Kung, Williams John P

机构信息

Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

出版信息

J Med Chem. 2005 Aug 11;48(16):5104-7. doi: 10.1021/jm050384+.

DOI:10.1021/jm050384+

PMID:16078829

Abstract

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.

摘要

本文讨论了三环咪唑并[4,5-b]吡啶-2-酮作为人促肾上腺皮质激素释放因子受体（CRF(1)）拮抗剂的合成及构效关系研究。化合物16g被鉴定为一种功能性拮抗剂，可抑制CRF刺激的环磷酸腺苷生成以及CRF诱导的促肾上腺皮质激素释放。大鼠体内的药代动力学研究表明，16g具有口服生物利用度，脑渗透性良好，半衰期适中。为了找到具有改善药代动力学性质的CRF(1)拮抗剂，16g表现出有利的较低分布容积。