Concepedia

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

Dustin S. Siegel, Hon C. Hui, Edward Doerffler, Michael O. Clarke, Kwon Soo Chun, Lijun Zhang, Sean Neville, Ernest Carra, Willard Lew, Bruce S. Ross,

Journal of Medicinal Chemistry · 2017 · 665 citations · 32 references

DOI Full text

Open access

TL;DR

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.