Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-<i>f</i>][triazin-4-amino] Adenine <i>C</i>-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

TLDR

The 2014–2016 West African Ebola outbreak was the largest ever, with over 28,000 cases and more than 11,000 deaths, including >500 healthcare workers. A phase 2 PREVAIL IV study is enrolling to assess 4b’s impact on viral shedding from sanctuary sites in Ebola survivors. Through focused screening and lead optimization, 4b (GS‑5734) was identified as a potent anti‑Ebola agent (EC50 = 86 nM), with structure‑activity studies showing the 1′‑CN group and C‑linked nucleobase essential for potency and host polymerase selectivity, and a diastereoselective synthesis enabled preclinical efficacy testing in non‑human primates. Daily 10 mg/kg IV dosing from days 3–14 post‑infection reduced viremia and mortality, achieving 100 % survival in treated non‑human primates.

Abstract

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016 , 531 , 381 - 385 ]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.