Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin
| Autor: | James M. Balkovec, Robert A. Giacobbe, Jennifer Nielsen Kahn, Ming Jo Hsu, Weiming Fan, Ahmed Mamai, Michael Robert Peel, James M. Apgar, Amy M. Flattery, Paul A. Liberator, Fred Racine, Bahanu Habulihaz, Mary Motyl, Kingsley H. Nelson, Robert R. Wilkening, Robin Kirwan, M A Powles, George K. Abruzzo, Andrew Galgoci, Charles Gill, Andrew S. Misura, Shu Lee, Jasminka Dragovic, Hao Liu, Mark L. Greenlee |
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| Rok vydání: | 2015 |
| Předmět: |
Antifungal Agents
beta-Glucans Clinical Biochemistry Administration Oral Pharmaceutical Science Microbial Sensitivity Tests Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics Candida albicans Drug Discovery Animals Moiety Potency Structure–activity relationship Glycosides Molecular Biology chemistry.chemical_classification Natural product biology Terpenes Aspergillus fumigatus Organic Chemistry Candidiasis Glycoside biology.organism_classification Triterpenes chemistry Glucosyltransferases Molecular Medicine Echinocandins Half-Life |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:5813-5818 |
| ISSN: | 0960-894X |
| Popis: | The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis. |
| Databáze: | OpenAIRE |
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