Farmer Luc J, Clark Michael P, Boyd Michael J, Perola Emanuele, Jones Steven M, Tsai Alice, Jacobs Marc D, Bandarage Upul K, Ledeboer Mark W, Wang Tiansheng, Deng Hongbo, Ledford Brian, Gu Wenxin, Duffy John P, Bethiel Randy S, Shannon Dean, Byrn Randal A, Leeman Joshua R, Rijnbrand Rene, Bennett Hamilton B, O'Brien Colleen, Memmott Christine, Nti-Addae Kwame, Bennani Youssef L, Charifson Paul S
Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
ACS Med Chem Lett. 2017 Jan 20;8(2):256-260. doi: 10.1021/acsmedchemlett.6b00486. eCollection 2017 Feb 9.
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound . Compound showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
在我们开发用于治疗流感的新型小分子抑制剂的过程中，我们利用分子建模和流感病毒聚合酶PB2亚基的X射线晶体结构来优化一系列无环β-氨基酸抑制剂，化合物 尤为突出。化合物 在大鼠和小鼠体内均表现出良好的口服暴露性。更重要的是，它对多种甲型流感病毒株具有强大的效力，包括2009年大流行的H1N1和禽流感H5N1毒株，并且在小鼠流感模型中显示出强大的疗效，即使在感染后48小时开始治疗也是如此。化合物 具有良好的口服生物利用度，在治疗大流行和季节性流感方面具有巨大潜力。
