Donner Pamela L, Xie Qinghua, Pratt John K, Maring Clarence J, Kati Warren, Jiang Wen, Liu Yaya, Koev Gennadiy, Masse Sherie, Montgomery Debra, Molla Akhter, Kempf Dale J
Antiviral Research, Global Pharmaceutical Research, and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Bioorg Med Chem Lett. 2008 Apr 15;18(8):2735-8. doi: 10.1016/j.bmcl.2008.02.064. Epub 2008 Mar 4.
In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure-activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.
在我们发现1型丙型肝炎病毒（HCV）聚合酶非核苷小分子抑制剂的项目中，我们基于一种含有ABCD环系的苯并噻二嗪筛选命中物研究了一系列有前景的类似物。在证明甲磺酰氨基D环取代基可将酶活性提高到低纳摩尔范围后，我们通过截短为三环系统来探索活性所需的最小核心。本文描述了一组缺少ABCD环系A环的抑制剂的合成及构效关系。我们观察到，连接在B环5位的小芳香环和烯基是最佳的，从而产生了具有低纳摩尔活性的抑制剂。
