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

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

  • Bioorg Med Chem Lett. 2021 Jan 15;32:127661. doi: 10.1016/j.bmcl.2020.127661.
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: 33160023 DOI: 10.1016/j.bmcl.2020.127661
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.

Keywords

Enfumafungin; Ibrexafungerp; MK-3118; SCY-078; β-1,3-glucan synthesis inhibitor.

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