2. Academic Validation
  3. Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity

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

Affiliation

  • 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.

Figures
Products