Design, Synthesis, and Structure鈥揂ctivity Relationships of Novel Pyrazolo[5,1-b]thiazole Derivatives as Potent and Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists

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• 作者：Yoshinori Takahashi ; Minako Hashizume ; Kogyoku Shin ; Taro Terauchi ; Kunitoshi Takeda ; Shigeki Hibi ; Kaoru Murata-Tai ; Masae Fujisawa ; Kodo Shikata ; Ryota Taguchi ; Mitsuhiro Ino ; Hisashi Shibata ; Masahiro Yonaga
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8450-8463
• 全文大小：438K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

This paper describes the design, synthesis, and structure鈥揳ctivity 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 (CRF₁) 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 (IC₅₀ = 70 nM) and functional antagonism (IC₅₀ = 7.1 nM) for the human CRF₁ 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).