Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5.
J Med Chem. 2014 Mar 13;57(5):1845-54. doi: 10.1021/jm4011862. Epub 2013 Nov 11.
Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.
采用柔性扭转角的构象限制来指导 HCV NS5B 抑制剂的新型化学型别鉴定。刚性化部位基于对化合物结合要求和取代基在游离和结合状态下作用的获得性构象理解。酰胺键的化学生物等排体被探索用于提高基于细胞的效力。包括导致发现 III 期临床候选药物 deleobuvir（BI 207127）的设计理念的实例。所采用的基于结构的策略在药物设计中具有普遍适用性。
