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.
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).
authors.affiliation: Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. y4-takahashi@hhc.eisai.co.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Minako
authors.initials: M
authors.lastname: Hashizume
authors.forename: Kogyoku
authors.initials: K
authors.lastname: Shin
authors.forename: Taro
authors.initials: T
authors.lastname: Terauchi
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Hibi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Murata-Tai
authors.forename: Masae
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Kodo
authors.initials: K
authors.lastname: Shikata
authors.forename: Ryota
authors.initials: R
authors.lastname: Taguchi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ino
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shibata
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yonaga
mesh_terms: D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003672:Defecation / Q000187:drug effects; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; C577117: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; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP