2. Academic Validation
  3. 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

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

  • J Med Chem. 2012 Oct 11;55(19):8450-63. doi: 10.1021/jm300864p.
Yoshinori Takahashi 1,  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
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. y4-takahashi@hhc.eisai.co.jp
PMID: 22971011 DOI: 10.1021/jm300864p
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).

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