Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors

  • J Med Chem. 2008 Nov 13;51(21):6642-5. doi: 10.1021/jm800986w.
Yangbo Feng  1 ,  Yan Yin ,  Amiee Weiser ,  Evelyn Griffin ,  Michael D Cameron ,  Li Lin ,  Claudia Ruiz ,  Stephan C Schürer ,  Toshihiro Inoue ,  P Vasanth Rao ,  Thomas Schröter ,  Philip Lograsso
Affiliations
  • 1. Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Florida, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
PMID: 18834107 DOI: 10.1021/jm800986w
Abstract

The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compound 5 (SR-3677) had an IC 50 of approximately 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.

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