新型促肾上腺皮质激素释放因子-1（CRF1）受体拮抗剂N3-苯基吡嗪酮的合成、构效关系及体内评价

Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

作者信息

Hartz Richard A, Ahuja Vijay T, Arvanitis Argyrios G, Rafalski Maria, Yue Eddy W, Denhart Derek J, Schmitz William D, Ditta Jonathan L, Deskus Jeffrey A, Brenner Allison B, Hobbs Frank W, Payne Joseph, Lelas Snjezana, Li Yu-Wen, Molski Thaddeus F, Mattson Gail K, Peng Yong, Wong Harvey, Grace James E, Lentz Kimberley A, Qian-Cutrone Jingfang, Zhuo Xiaoliang, Shu Yue-Zhong, Lodge Nicholas J, Zaczek Robert, Combs Andrew P, Olson Richard E, Bronson Joanne J, Mattson Ronald J, Macor John E

机构信息

Research and Development, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492, USA.

出版信息

J Med Chem. 2009 Jul 23;52(14):4173-91. doi: 10.1021/jm900301y.

DOI:10.1021/jm900301y

PMID:19552437

Abstract

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.

摘要

有证据表明，促肾上腺皮质激素释放因子-1（CRF(1)）受体拮抗剂可能为治疗与CRF水平升高相关的疾病（如焦虑症和抑郁症）提供治疗潜力。发现了一种基于吡嗪酮的CRF(1)受体拮抗剂化学类型。构效关系研究导致鉴定出许多强效类似物，包括12p，一种强效且选择性的CRF(1)受体拮抗剂，IC(50)值为0.26 nM。在大鼠和食蟹猴中评估了12p的药代动力学特性。化合物12p在大鼠的防御性回避试验（一种焦虑动物模型）中有效。描述了吡嗪酮化学类型内化合物的合成、构效关系和体内性质。