Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

…, R Pireddu, NJ Lawrence, J Li, EB Haura…

Index: Li, Rongshi; Martin, Mathew P.; Liu, Yan; Wang, Binglin; Patel, Ronil A.; Zhu, Jin-Yi; Sun, Nan; Pireddu, Roberta; Lawrence, Nicholas J.; Li, Jiannong; Haura, Eric B.; Sung, Shen-Shu; Guida, Wayne C.; Schonbrunn, Ernst; Sebti, Said M. Journal of Medicinal Chemistry, 2012 , vol. 55, # 5 p. 2474 - 2478

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Citation Number: 34

Abstract

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC50= 650 nM) and ROCK2 (IC50= 670 nM), whereas compound 24 was more selective for ROCK2 (IC50= 100 nM) over ROCK1 (IC50= 1690 nM). The crystal structure of the compound 18–ROCK1 complex revealed that 18 is a type ...