8-（4-甲氧基苯基）吡唑并[1,5-a]-1,3,5-三嗪：选择性中枢活性促肾上腺皮质激素释放因子受体-1（CRF1）拮抗剂。

8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists.

作者信息

Gilligan Paul J, He Liqi, Clarke Todd, Tivitmahaisoon Parcharee, Lelas Snjezana, Li Yu-Wen, Heman Karen, Fitzgerald Lawrence, Miller Keith, Zhang Ge, Marshall Anne, Krause Carol, McElroy John, Ward Kathyrn, Shen Helen, Wong Harvey, Grossman Scott, Nemeth Gregory, Zaczek Robert, Arneric Stephen P, Hartig Paul, Robertson David W, Trainor George

机构信息

Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, Connecticut 06492, USA.

出版信息

J Med Chem. 2009 May 14;52(9):3073-83. doi: 10.1021/jm9000242.

DOI:10.1021/jm9000242

PMID:19361210

Abstract

This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.

摘要

本报告描述了8-(4-甲氧基苯基)吡唑并[1,5-a]-1,3,5-三嗪促肾上腺皮质激素释放因子受体-1（CRF(1)）受体拮抗剂的合成及其构效关系。CRF(1)受体拮抗剂可能是潜在的抗焦虑或抗抑郁药物。该研究最终发现了类似物12-3，它是一种强效、选择性的CRF(1)拮抗剂（人CRF(1)的IC(50)=4.7±2.0 nM），对CRF结合蛋白和生物胺受体的亲和力较弱。该化合物在犬类中也具有良好的药代动力学特征。类似物12-3在两种大鼠焦虑模型中口服有效：防御性退缩（情境性焦虑）模型和高架十字迷宫试验。类似物12-3已进入临床试验阶段。