ABSTRACT
The echinocandin class of cyclic lipopeptides has been simplified to discover potent antifungal compounds. Namely A-192411 shows good in vitro activity against common pathogenic yeasts and has an acceptable safety window in vivo. Discovery, limited SAR, synthesis, biochemical and pharmaco-dynamic profiles of A-192411 are presented.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/metabolism , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Animals , Antifungal Agents/pharmacokinetics , Area Under Curve , Candida/drug effects , Candida/metabolism , Candidiasis/drug therapy , Candidiasis/microbiology , Chemical Phenomena , Chemistry, Physical , Dogs , Drug Design , Fungi/drug effects , Glucans/metabolism , Haplorhini , Mice , Microbial Sensitivity Tests , Oligopeptides/pharmacokinetics , RNA, Fungal/biosynthesis , Rats , Structure-Activity RelationshipABSTRACT
The ability of the novel antifungal cyclic hexalipopetide A-192411 to treat fungal infections in rodents is presented. Efficacy was demonstrated against Candida albicans as both prolonged survival of systemically infected mice and clearance of viable yeasts from kidneys. The efficacy of A-192411, administered intraperitoneally, was equivalent to amphotercin B at a 4-fold lower dose by weight in the systemic candidiasis models in mice, while the efficacy of A-192441 administered intravenously was equivalent to amphotercin B by weight in the Candida pyelonephritis model in rats. A-192411 also slightly prolonged the survival of immunocompromised mice infected systemically with Aspergillus fumigatus.
