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Design, synthesis and antifungal activity of the novel water-soluble prodrug of antifungal triazole CS-758.

Authors
  • Kagoshima, Yoshiko
  • Mori, Makoto
  • Suzuki, Eiko
  • Kobayashi, Nobue
  • Shibayama, Takahiro
  • Kubota, Mikie
  • Kamai, Yasuki
  • Konosu, Toshiyuki
Type
Published Article
Journal
Chemical and Pharmaceutical Bulletin
Publisher
Pharmaceutical Society of Japan
Publication Date
Jun 01, 2010
Volume
58
Issue
6
Pages
794–804
Identifiers
PMID: 20522989
Source
Medline
License
Unknown

Abstract

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).

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