RESUMEN
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.
Asunto(s)
Aminopiridinas/farmacología , Antifúngicos/farmacología , Cryptococcus/efectos de los fármacos , Isoxazoles/farmacología , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Aminopiridinas/síntesis química , Aminopiridinas/química , Antifúngicos/síntesis química , Antifúngicos/química , Relación Dosis-Respuesta a Droga , Proteínas Fúngicas , Isoxazoles/síntesis química , Isoxazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Proteínas de Saccharomyces cerevisiae/metabolismo , Relación Estructura-ActividadRESUMEN
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.