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Antimicrobial Agents and Chemotherapy, September 2004, p. 3272-3278, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3272-3278.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Novel Azole R126638 Is a Selective Inhibitor of Ergosterol Synthesis in Candida albicans, Trichophyton spp., and Microsporum canis

Hugo Vanden Bossche,^1, Jannie Ausma,^2* Hilde Bohets,¹ Karen Vermuyten,¹ Gustaaf Willemsens,¹ Patrick Marichal,¹ Lieven Meerpoel,¹ Frank Odds,³ and Marcel Borgers²

Johnson and Johnson Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica, Beerse,¹ Barrier Therapeutics, Geel, Belgium,² School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom³

Received 23 April 2004/ Returned for modification 20 May 2004/ Accepted 26 May 2004

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 Microsporum canis at nanomolar concentrations, with 50% inhibitory concentrations (IC₅₀s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14-methyl group of lanosterol or eburicol. The IC₅₀s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 µM for itraconazole and 3.1 µM for R126638. Compared to itraconazole (IC₅₀ = 3.5 µM), R126638 is a poor inhibitor of the 1-hydroxylation of 25-hydroxyvitamin D₃ (IC₅₀ > 10 µM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D₃ and the conversion of 1,25-dihydroxyvitamin D₃ into polar metabolites. At concentrations up to 10 µM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11ß-hydroxylase (CYP11B1), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 µM, R126638 did not show clear inhibition of CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6ß 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.

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* Corresponding author. Mailing address: Barrier Therapeutics nv, Cipalstraat, 3, B2440 Geel, Belgium. Phone: 32 14 570524. Fax: 32 14 570515. E-mail: jausma{at}barriertherapeutics.com.

Present address: Steenweg op Gierle, 68, B2300 Turnhout, Belgium.

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Antimicrobial Agents and Chemotherapy, September 2004, p. 3272-3278, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3272-3278.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.