Design, synthesis and antifungal activity of the novel water-soluble prodrug of antifungal triazole CS-758.
CS-758 was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, phosphoryl ester prodrugs were designed. In this study, the synthesis and evaluation of these injectable prodrugs are described. Phosphoryl ester 17 h was soluble in water, and was stable in both water and in a solid state. 17 h was converted to CS-758 in human liver microsome and was also converted to CS-758 in rats after intravenous (i.v.) administration with good conversion speed and efficiency. 17 h (i.v.) reduced the viable cell counts in kidneys in a murine hematogenous Candida albicans infection model and in lungs in a murine pulmonary Aspergillus fumigatus infection model, wherein the effects were comparable to or slightly superior to that of CS-758 (per os).
Kagoshima
Yoshiko
Y
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.
Mori
Makoto
M
Suzuki
Eiko
E
Kobayashi
Nobue
N
Shibayama
Takahiro
T
Kubota
Mikie
M
Kamai
Yasuki
Y
Konosu
Toshiyuki
T
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009181:Mycoses / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D012995:Solubility; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000935:Antifungal Agents; D011355:Prodrugs; D014230:Triazoles; C453343:R-120758