title: Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 2: Synthesis and inhibitory activity of aryl-3-trifluoromethylpyrazoles.
abstract: To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yasuhiro.yonetoku@jp.astellas.com
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonetoku
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kubota
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D003208:Concanavalin A / Q000737:chemistry; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000517:prevention & control; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D010853:Picryl Chloride / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011720:Pyrazoles; D003208:Concanavalin A; D002118:Calcium; D010853:Picryl Chloride