R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microspgrum canis at nanomolar concentrations, with 50% inhibitory concentrations IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 muM for itraconazole and 3.1 muM for R126638. Compared to itraconazole (IC50 = 3.5 muM), R126638 is a poor inhibitor of the 1alpha-hydroxylation of 25-hydroxyvitamin D-3 IC50 > 10 muM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D-3, and the conversion of 1,1,25-dihydroxyvitamin D-3, into polar metabolites. At concentrations up to 10 muM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11beta-hydroxylase (CYPHBII), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 muM, R126638 did not show clear inhibition of CYP1A2,CYP2A6,CYP26,CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.
- HUMAN LIVER-MICROSOMES
- ANTIFUNGAL AGENTS