Document Report Card

ID: ALA1139215

Journal: J Med Chem

Title: Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.

Authors: Stavenger RA, Cui H, Dowdell SE, Franz RG, Gaitanopoulos DE, Goodman KB, Hilfiker MA, Ivy RL, Leber JD, Marino JP, Oh HJ, Viet AQ, Xu W, Ye G, Zhang D, Zhao Y, Jolivette LJ, Head MS, Semus SF, Elkins PA, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Doe CP, Bentley R, Chen ZX, Hu E, Lee D.

Abstract: 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.

CiteXplore: 17201404

DOI: 10.1021/jm060873p