Document Report Card

ID: ALA2177001

Journal: J Med Chem

Title: Design, synthesis, and structure-activity relationships of novel pyrazolo[5,1-b]thiazole derivatives as potent and orally active corticotropin-releasing factor 1 receptor antagonists.

Authors: Takahashi Y, Hashizume M, Shin K, Terauchi T, Takeda K, Hibi S, Murata-Tai K, Fujisawa M, Shikata K, Taguchi R, Ino M, Shibata H, Yonaga M.

Abstract: This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).

CiteXplore: 22971011

DOI: 10.1021/jm300864p