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

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).

• Authors: Yoshiko Kagoshima, Makoto Mori, Eiko Suzuki, Nobue Kobayashi, Takahiro Shibayama, Mikie Kubota, Yasuki Kamai, Toshiyuki Konosu
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 58 Issue 6 Pg. 794-804 (Jun 2010) ISSN: 1347-5223 [Electronic] Japan
• PMID: 20522989 (Publication Type: Journal Article)

Chemical References

• Antifungal Agents
• Prodrugs
• Triazoles
• R-120758

Topics

• Animals
• Antifungal Agents (chemistry, metabolism, pharmacokinetics, therapeutic use)
• Aspergillosis (drug therapy)
• Aspergillus fumigatus (drug effects)
• Candida albicans (drug effects)
• Candidiasis (drug therapy)
• Humans
• Mice
• Microsomes, Liver (metabolism)
• Mycoses (drug therapy)
• Prodrugs (chemistry, metabolism, pharmacokinetics, therapeutic use)
• Rats
• Solubility
• Triazoles (chemistry, metabolism, pharmacokinetics, therapeutic use)