ABSTRACT
We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious ß-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.
Subject(s)
Antifungal Agents/pharmacology , Aspergillus/drug effects , Candida albicans/drug effects , Glycosides/chemistry , Triterpenes/chemistry , beta-Glucans/metabolism , Administration, Oral , Animals , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Candidiasis/drug therapy , Disease Models, Animal , Glycosides/pharmacokinetics , Glycosides/pharmacology , Glycosides/therapeutic use , Half-Life , Mice , Structure-Activity Relationship , Triterpenes/pharmacokinetics , Triterpenes/pharmacology , Triterpenes/therapeutic useABSTRACT
Our previously reported efforts to produce an orally active ß-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.
Subject(s)
Antifungal Agents/chemistry , Triazoles/chemistry , beta-Glucans/metabolism , Administration, Oral , Animals , Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis/drug therapy , Disease Models, Animal , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Glycosides/chemistry , Half-Life , Mice , Microbial Sensitivity Tests , Stereoisomerism , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacology , Triazoles/therapeutic use , Triterpenes/chemistry , beta-Glucans/chemistryABSTRACT
A series of 2-9a bridged tetrahydrofluorenone derivatives were prepared which exhibited significant binding affinity for ERbeta and were highly selective.
