Yu Wensheng, Zhou Guowei, Coburn Craig A, Zeng Qingbei, Tong Ling, Dwyer Michael P, Hu Bin, Zhong Bin, Hao Jinglai, Ji Tao, Zan Shuai, Chen Lei, Mazzola Robert, Kim Jae-Hun, Sha Deyou, Selyutin Oleg, Rosenblum Stuart B, Lavey Brian, Nair Anilkumar G, Heon Kim Seong, Keertikar Kerry M, Rokosz Laura, Agrawal Sony, Liu Rong, Xia Ellen, Zhai Ying, Curry Stephanie, McMonagle Patricia, Ingravallo Paul, Asante-Appiah Ernest, Chen Shiying, Kozlowski Joseph A
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2016 Oct 1;26(19):4851-4856. doi: 10.1016/j.bmcl.2016.08.002. Epub 2016 Aug 2.
As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
作为默克公司在NS5A抑制方面持续努力的一部分，我们现在描述我们在MK - 8742的四环吲哚核心周围引入取代基的工作。核心上的氟取代与脯氨酸环上的氟取代相结合，显著提高了对GT1a Y93H的效力。然而，GT2b效力没有得到改善。将氟取代限制在四环吲哚核心的C - 1位，对针对耐药相关变体（如GT1a Y93H和GT2b）的效力以及药代动力学特征都有积极影响。我们鉴定出了一些化合物，如62，它们在野生型GT1a与GT2b、GT1a Y93H和GT1a L31V之间的效力变化较小。
