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

Siegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L.

[Image: see text] 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 EC(50) = 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 [Nature2016, 531, 381−38526934220]. 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.