Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) Inhibitors

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• 作者：Yangbo Feng ; Yan Yin ; Amiee Weiser ; Evelyn Griffin ; Michael D. Cameron ; Li Lin ; Claudia Ruiz ; Stephan C. Schü ; rer ; Toshihiro Inoue ; P. Vasanth Rao ; Thomas Schrö ; ter ; Philip LoGrasso
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：November 13, 2008
• 年：2008
• 卷：51
• 期：21
• 页码：6642-6645
• 全文大小：139K
• 年卷期：v.51,no.21(November 13, 2008)
• ISSN：1520-4804

文摘

The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compound 5 (SR-3677) had an IC₅₀ of ∼3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacology studies showed that 5 was efficacious in both, increasing ex vivo aqueous humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.