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

作者：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

来源：Journal of Medicinal Chemistry, 2017, 60(5): 1648-1661.

DOI：10.1021/acsjmecichem.6b01594

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 l'-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.

• 出版日期2017-3-9