In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum

Abstract

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.

Review of Newer Antifungal and Immunomodulatory Strategies for Invasive Aspergillosis

“…Penetration of ravuconazole into healthy rat tissue showed that the concentration of drug in the lungs was 2-6 times higher than the corresponding blood concentration [235]. Another murine model revealed similar survival efficacy with itraconazole when both were given at 40 mg/ kg, but ravuconazole was better when both were compared at 10 mg/kg [236]. In a guinea pig model of disseminated aspergillosis, ravuconazole as well as itraconazole (10 mg/kg/day) displayed 100% survival (8 of 8 animals), compared with 87% survival with amphotericin B at 1.25 mg/kg/day ip.…”

The Mechanistic Targets of Antifungal Agents: An Overview

“…Several related agents are reported in the literature and include non-azole inhibitors of P-450DM that apparently have not been pursued further [42]. Other notable agents include SCH-56592 (posaconazole), a triazole which was first presented at the 1995 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting by Schering-Plough [43]; TAK-187, an optically active azolone triazole [1]; ER-30346, a thiazole, which was shown in vitro to be more potent than itraconazole against C. albicans, C. parapsilosis, C. glabrata, Trichosporon beigelli, A. fumigatus, and C. neoformans [44]; and T-8581, a triazole amide [45], which is highly water-soluble and active against C. neoformans and C. albicans .…”

Advances in synthetic approach to and antifungal activity of triazoles

“…Voriconazole also shows non-linear pharmacokinetics but has raised some concern with respect to its ocular toxicity. ER 30346 shows the best anti-aspergillus activity, SCH 56592 is a hydroxylated analogue of itraconazole with potent in vitro and in vivo activity [74–75]. …”