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

  • J Med Chem. 2007 Jan 11;50(1):2-5. doi: 10.1021/jm060873p.
Robert A Stavenger  1 ,  Haifeng Cui ,  Sarah E Dowdell ,  Robert G Franz ,  Dimitri E Gaitanopoulos ,  Krista B Goodman ,  Mark A Hilfiker ,  Robert L Ivy ,  Jack D Leber ,  Joseph P Marino Jr ,  Hye-Ja Oh ,  Andrew Q Viet ,  Weiwei Xu ,  Guosen Ye ,  Daohua Zhang ,  Yongdong Zhao ,  Larry J Jolivette ,  Martha S Head ,  Simon F Semus ,  Patricia A Elkins ,  Robert B Kirkpatrick ,  Edward Dul ,  Sanjay S Khandekar ,  Tracey Yi ,  David K Jung ,  Lois L Wright ,  Gary K Smith ,  David J Behm ,  Christopher P Doe ,  Ross Bentley ,  Zunxuan X Chen ,  Erding Hu ,  Dennis Lee
Affiliations
  • 1. Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. [email protected]
PMID: 17201404 DOI: 10.1021/jm060873p
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.

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