SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-␤-cyclodextrin (HP␤CD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HP␤CD solution (range, 52 to ϳ100%) than from the MC suspension (range, 14 to 48%) and was higher in mice (ϳ100% [HP␤CD] ). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.The incidence of fungal infections has substantially increased over the past 2 decades, and invasive forms are important causes of morbidity and mortality (1). Of the estimated 100,000 known species of fungi, about 180 have been shown to cause disease in humans, and only about 10% of these are encountered in most clinical settings (2). Disseminated candidiasis, pulmonary aspergillosis, and infections caused by emerging opportunistic fungi are the most common of the serious mycoses (12). Aggressive immunosuppression, myelotoxic therapeutic regimens, AIDS, cancer, and organ transplantation have opened the door for these organisms. Although amphotericin B has been the gold standard in antifungal therapy for half of a century, newer chemical agents, such as azoles, have emerged in recent decades. These entities are generally active by more than one route of administration, have a broader spectrum of activity, and are less toxic than amphotericin B. The ideal antifungal agent would be broad spectrum, fungicidal, active against resistant strains, and active by various routes of administration and would have a good safety profile.SCH 56592 has been shown to be active against both yeasts and filamentous fungi, including Aspergillus, Candida (including fluconazole-resistant Candida krusei), Cryptococcus, Blastomyces, Coccidioides...

No abstract

Herein we describe structure−activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4-and 6positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.

Rapid, generic gradient liquid chromatography/tandem mass spectrometry (LC/MS/MS) assays, designed to accelerate sample analyses, have been developed to keep pace with the productivity of advanced synthetic procedures. In this study, LC/MS/MS was combined with an in vitro, cell-based, blood-brain barrier (BBB) model to evaluate the potential of new chemical entities (NCEs) to cross the BBB. This in vitro assay provides the permeability of discovery compounds across a monolayer of a primary culture of bovine brain microvessel endothelial cells in a fraction of the time that is required for in vivo studies (brain/plasma concentrations), using only 2 mg of the compound. The results are consistent with in vivo brain/plasma concentration ratio data.

No abstract