2. Academic Validation
  3. MK-5204: An orally active β-1,3-glucan synthesis inhibitor

MK-5204: An orally active β-1,3-glucan synthesis inhibitor

  • Bioorg Med Chem Lett. 2020 Sep 1;30(17):127357. doi: 10.1016/j.bmcl.2020.127357.
James M Apgar 1,  Robert R Wilkening 2,  Dann L Parker Jr 2,  Dongfang Meng 2,  Kenneth J Wildonger 2,  Donald Sperbeck 2,  Mark L Greenlee 2,  James M Balkovec 2,  Amy M Flattery 2,  George K Abruzzo 2,  Andrew M Galgoci 2,  Robert A Giacobbe 2,  Charles J Gill 2,  Ming-Jo Hsu 2,  Paul Liberator 2,  Andrew S Misura 2,  Mary Motyl 2,  Jennifer Nielsen Kahn 2,  Maryann Powles 2,  Fred Racine 2,  Jasminka Dragovic 2,  Weiming Fan 3,  Robin Kirwan 3,  Shu Lee 3,  Hao Liu 3,  Ahmed Mamai 3,  Kingsley Nelson 3,  Michael Peel 3
Affiliations

Affiliations

  • 1 Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: james_apgar@merck.com.
  • 2 Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 3 Scynexis Inc., 1 Evertrust Plaza, Jersey City, NJ 07302, USA.
PMID: 32738971 DOI: 10.1016/j.bmcl.2020.127357
Abstract

Our previously reported efforts to produce an orally active β-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.

Keywords

Antifungal; Candidiasis; Enfumafungin; MK-5204; β-1,3-Glucan synthesis inhibitor.

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