1. Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor
- Author
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Dongfang Meng, Dann L. Parker, Robin Kirwan, M A Powles, Jennifer Nielsen Kahn, James M. Apgar, Fred Racine, Paul A. Liberator, Amy M. Flattery, Andrew Galgoci, Kingsley H. Nelson, James M. Balkovec, Andrew S. Misura, Weiming Fan, Donald M. Sperbeck, Michael Robert Peel, Robert A. Giacobbe, Mark L. Greenlee, Ahmed Mamai, Jasminka Dragovic, Kenneth J. Wildonger, Hao Liu, Robert R. Wilkening, Mary Motyl, Shu Lee, Ming-Jo Hsu, Charles Gill, and George K. Abruzzo more...
- Subjects
β 1 3 glucan ,Antifungal Agents ,beta-Glucans ,medicine.drug_class ,Clinical Biochemistry ,Triazole ,Substituent ,Pharmaceutical Science ,Phases of clinical research ,Administration, Oral ,Carboxamide ,Pharmacology ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Candida albicans ,medicine ,Animals ,Aspergillosis ,Glycosides ,Molecular Biology ,Natural product ,010405 organic chemistry ,Organic Chemistry ,Candidiasis ,Enfumafungin ,Triterpenes ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Disease Models, Animal ,Orally active ,Aspergillus ,chemistry ,Molecular Medicine ,Half-Life - Abstract
We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-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. more...
- Published
- 2020