Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK.
Bioorg Med Chem Lett. 2011 Feb 15;21(4):1084-8. doi: 10.1016/j.bmcl.2010.12.104. Epub 2010 Dec 28.
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Rho 激酶是一种与多种心血管疾病相关的重要靶点。在此，我们报告了片段衍生的 ATP 竞争性 ROCK 抑制剂 1 和 2 向先导化合物 14A 的优化。最初的目标是提高 ROCK-I 的效力相对于 1，同时保持良好的 PK 特性，通过去除氨基异喹啉的碱性中心来实现。先导化合物 14A 对 ROCK-I 和 ROCK-II 均具有等效活性，在自发性高血压大鼠模型中显示出良好的体内疗效，并进一步优化以证明与羟基法舒地尔 3 相比提高对 PKA 选择性的范围。
