title: Optically active antifungal azoles. VII. Synthesis and antifungal activity of stereoisomers of 2-[(1R,2R)-2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazo lone (TAK-187).
abstract: 2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]-4-[4-(2,2,3,3,tetrafluoropropoxy) phenyl]-3(2H, 4H)-1,2,4-triazolone [(1R,2R)-1: TAK-187] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2S)-, (1R,2S)- and (1S,2R)-1] of this compound were prepared to clarify the relationship between the stereochemistry and the biological activities. In vitro and in vivo assays of antifungal activity revealed that TAK-187 [(1R,2R)-1] is the most potent among the four stereoisomers. Furthermore, TAK-187 was found to exert strong and selective inhibitory effect on the sterol synthesis in Candida albicans as compared with that in rat liver.
authors.affiliation: Pharmaceutical Research Laboratories III, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tasaka
authors.forename: T
authors.initials: T
authors.lastname: Kitazaki
authors.forename: N
authors.initials: N
authors.lastname: Tsuchimori
authors.forename: Y
authors.initials: Y
authors.lastname: Matsushita
authors.forename: R
authors.initials: R
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Okonogi
authors.forename: K
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002176:Candida albicans / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D051381:Rats; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry; D005466:Fluorocarbons
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C105227:TAK 187; D005466:Fluorocarbons