Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6063-6. doi: 10.1016/j.bmcl.2012.08.049. Epub 2012 Aug 21.
In a previous disclosure,(1) we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.
在之前的一份披露中，(1) 我们报告了亚胺噻唑烷酮的二聚化形成 1，这是观察到 HCV 基因型 1b 复制子活性抑制的原因之一。二聚体通过基于生物测定的分馏实验分离出来，并被证明是一种有效的基因型 1b HCV 复制抑制剂，其耐药性与 NS5A 蛋白有关。在结构简化的二苯乙烯脯氨酰胺 2 中成功捕获了负责控制 HCV 抑制活性的元素。本文描述了与二苯乙烯脯氨酰胺相关的早期 SAR 和特性研究，最终确定了具有足够 PK 特性的类似物，值得继续致力于这一化学型。这些研究代表了发现达卡他韦（BMS-790052）的关键初始步骤，该化合物已证明在抑制 HCV 感染中 NS5A 复制复合物方面具有临床概念验证。
