Beaulieu Pierre L, Bolger Gordon, Duplessis Martin, Gagnon Alexandre, Garneau Michel, Stammers Timothy, Kukolj George, Duan Jianmin
Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
Bioorg Med Chem Lett. 2015 Mar 1;25(5):1135-9. doi: 10.1016/j.bmcl.2014.12.028. Epub 2014 Dec 17.
A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
对强效丙型肝炎病毒NS5B聚合酶拇指口袋1抑制剂BI 207524（2）的一系列杂环氮类似物进行了研究，目的是减少与体内释放具有基因毒性的苯胺代谢物相关的风险。鉴定出在艾姆斯试验中呈阴性的含有2-氨基吡啶苯胺等排体的类似物4，发现其对GT1a/1b的效力与2相当。尽管类似物4的跨物种药代动力学特征、预测的人肝分布较差以及异速生长原理表明需要高剂量才能在患者中实现强效抗病毒反应，但这项工作为设计具有更好安全性的新型拇指口袋1 NS5B聚合酶抑制剂提供了一条前进的道路。
