Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5.
Bioorg Med Chem Lett. 2013 Jun 1;23(11):3401-5. doi: 10.1016/j.bmcl.2013.03.074. Epub 2013 Apr 3.
Detailed structure-activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identification of the most potent compound in the series, analog 27. Productive SAR also transferred to the benzotriazepine and spirobenzodiazepine scaffolds, providing a solution to the labile stereocenter at the C3 position. The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed.
描述了一系列苯并[1,4]二氮杂环庚二酮抑制剂对 HIV 衣壳（CA）组装的抗病毒效力的 C3-苯基部分的详细结构-活性关系。有利取代的组合产生了加和性 SAR，并确定了该系列中最有效的化合物，类似物 27。生产性 SAR 也转移到苯并三氮唑和螺苯并二氮杂环庚烷骨架上，为 C3 位置不稳定的立体中心提供了解决方案。利用高分辨率结构信息，合理地解释了化合物 27 如何抑制成熟 CA 组装的分子基础。还讨论了化合物 27 如何抑制不成熟 Gag 组装的分子基础。
