RO0098557, a Novel Water Soluble Azole Prodrug for Parenteral and Oral Administration (I) Design, Synthesis, Physicochemical Properties and Bioconversion

J. OHWADA, M. TSUKAZAKI, T. HAYASE, N. OIKAWA, Y. ISSHIKI, Y. SHIRATORI, T. YAMAZAKI, S. ICHIHARA, I. UMEDA, M. ARISAWA and N. SHIMMA

Author address: 

Nippon Roche Research Center, Kamakura, Japan

Abstract: 

Background: There is a high medical need for a well tolerated parenteral form of a broad spectrum antifungal forthe treatment of severe deep mycoses of hospitalized patients. Current antifungal agents available for parenteral use have limitations in antifungal spectrum and safety, respectively. RO0094815 (1) is a new triazole with a broad antifungal spectrum. However, its low water solubility (<0.1μg/mL) restricts its use to the oral route.

Methods: To improve its water solubility, a series of prodrugs were synthesized to generate the active drug (1) by hydrolysis in plasma followed by intramolecular rearrangement of an intermediate (3). The physicochemical properties and conversion rates in rat, monkey and human plasma of the prodrugs have been studied.

Results: Among all prodrugs, RO0098557 (2), a triazolium salt type prodrug of 1 was selected because it has a high water solubility (>1g/mL) and sufficient chemical stability for parenteral use. 2 was quickly and stoichiometrically converted into 1 in human plasma (T1/2 = < 1 min).

Conclusions: The triazolium prodrug exhibits high water solubility, chemical stability, and fast and quantitative bioconversion to the active drug and has therefore, the appropriate profile for a new parenteral antifungal agent.

    • ICAAC 42nd