title: Synthesis, cleavage, and antifungal activity of a number of novel, water-soluble ester prodrugs of antifungal triazole CS-758.
abstract: In this study, the synthesis and evaluation of a number of esters of CS-758 as injectable prodrugs are described. Phosphoryl ester 1a was soluble in water (>30mg/mL) and was converted to CS-758 in human liver microsome. It was also converted to CS-758 in rats after iv administration, wherein the bioavailability of CS-758 was 53%. Compound 1a (iv) reduced the viable cell counts in kidneys in a murine systemic Candida albicans infection model, wherein the effect was comparable to or slightly superior to that of CS-758 (po). The prodrug 1a proved to be a promising injectable antifungal agent whose further evaluation is warranted.
authors.affiliation: Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kagoshima
authors.forename: Makoto
authors.initials: M
authors.lastname: Mori
authors.forename: Eiko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibayama
authors.forename: Tamako
authors.initials: T
authors.lastname: Iida
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kamai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Konosu
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002177:Candidiasis / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D011355:Prodrugs; D014230:Triazoles; C453343:R-120758; D014867:Water