Bioorganic and Medicinal Chemistry Letters (2021)
Update date:2022-08-04
Topics:
Apgar, James M.
Wilkening, Robert R.
Parker, Dann L.
Meng, Dongfang
Wildonger, Kenneth J.
Sperbeck, Donald
Greenlee, Mark L.
Balkovec, James M.
Flattery, Amy M.
Abruzzo, George K.
Galgoci, Andrew M.
Giacobbe, Robert A.
Gill, Charles J.
Hsu, Ming-Jo
Liberator, Paul
Misura, Andrew S.
Motyl, Mary
Nielsen Kahn, Jennifer
Powles, Maryann
Racine, Fred
Dragovic, Jasminka
Fan, Weiming
Kirwan, Robin
Lee, Shu
Liu, Hao
Mamai, Ahmed
Nelson, Kingsley
Peel, Michael
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.
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