Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in vitro evaluation against Cryptococcus spp

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126713. doi: 10.1016/j.bmcl.2019.126713. Epub 2019 Oct 14.

Abstract

Fosmanogepix (APX001) is a first-in-class prodrug molecule that is currently in Phase 2 clinical trials for invasive fungal infections. The active moiety manogepix (APX001A) inhibits the novel fungal protein Gwt1. Gwt1 catalyzes an early step in the GPI anchor biosynthesis pathway. Here we describe the synthesis and evaluation of 292 new and 24 previously described analogs that were synthesized using a series of advanced intermediates to allow for rapid analoging. Several compounds demonstrated significantly (8- to 32-fold) improved antifungal activity against both Cryptococcus neoformans and C. gattii as compared to manogepix. Further in vitro characterization identified three analogs with a similar preliminary safety and in vitro profile to manogepix and superior activity against Cryptococcus spp.

Keywords: APX001; APX001A; Antifungal; Cryptococcus; Fosmanogepix; GPI anchor biosynthesis; Gwt1; MGX; Manogepix.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Cryptococcus / drug effects*
  • Dose-Response Relationship, Drug
  • Fungal Proteins
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • APX001A
  • Aminopyridines
  • Antifungal Agents
  • Fungal Proteins
  • GWT1 protein, S cerevisiae
  • Isoxazoles
  • Saccharomyces cerevisiae Proteins