Stavenger Robert A, Cui Haifeng, Dowdell Sarah E, Franz Robert G, Gaitanopoulos Dimitri E, Goodman Krista B, Hilfiker Mark A, Ivy Robert L, Leber Jack D, Marino Joseph P, Oh Hye-Ja, Viet Andrew Q, Xu Weiwei, Ye Guosen, Zhang Daohua, Zhao Yongdong, Jolivette Larry J, Head Martha S, Semus Simon F, Elkins Patricia A, Kirkpatrick Robert B, Dul Edward, Khandekar Sanjay S, Yi Tracey, Jung David K, Wright Lois L, Smith Gary K, Behm David J, Doe Christopher P, Bentley Ross, Chen Zunxuan X, Hu Erding, Lee Dennis
Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
J Med Chem. 2007 Jan 11;50(1):2-5. doi: 10.1021/jm060873p.
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
本文介绍了一类新型Rho激酶抑制剂的发现、提出的结合模式及优化过程。在氮杂苯并咪唑核心结构的6位进行适当取代，可在体外提供亚纳摩尔级别的酶活性，同时显著提高对其他一系列激酶的选择性。已获得了最具活性和选择性的化合物的药代动力学数据，其中一种化合物（6n）已在高血压大鼠模型中显示出能降低血压的作用。
