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

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

Michael Trzoss  1 , Jonathan A Covel  2 , Mili Kapoor  2 , Molly K Moloney  2 , Quinlyn A Soltow  2 , Peter J Webb  2 , Karen Joy Shaw  3
Affiliations

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

Michael Trzoss et al. Bioorg Med Chem Lett. .

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.

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Conflict of interest statement

Conflict of interest statement. The authors are current employees of Amplyx Pharmaceuticals which has Gwt1 antifungal programs.

Figures

Figure 1.
Figure 1.
Structural elements of Gwt1 inhibitors and rationale for designing novel analogs.
Scheme 1.
Scheme 1.
Synthesis of advanced intermediates I to V. Reagents and conditions: (i) 2 M sodium carbonate in water, palladium(0)tetrakis(triphenylphosphine), dimethoxyethane, 90 °C; (ii) formic acid, 21–25 °C; (iii) 12 M aq. HCl, dioxane, reflux; (iv) 4 M aq. HCl, dioxane, 50 °C.
Scheme 2.
Scheme 2.
Representative examples for the synthesis of analogs from intermediate I. Reagents and conditions: (i) 2 M sodium carbonate in water, palladium(0)tetrakis(triphenylphosphine), dimethoxyethane, 90 °C, analogous procedures for 8b–8e; (ii) sodium hydride (60% in mineral oil), NMP, 21–25 °C then 50 °C, analogous procedure for 9b; (iii) DMF, 90 °C, analogous procedure for 10b.
Scheme 3.
Scheme 3.
Representative examples for the synthesis of analogs from intermediates II to V. Reagents and conditions: (i) N-ethyl-N-isopropylpropan-2-amine, DMSO, 120 °C, analogous procedure for 11b; (ii) potassium tert-butoxide (1M in THF), DMF, 21–25 °C then 90 °C, analogous procedures for 12b–12d; (iii) potassium tert-butoxide (1 M in THF), analogous procedures for 13b-13n and 14b.
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