Potent, selective and orally bioavailable dihydropyrimidine inhibitors of Rho kinase (ROCK1) as potential therapeutic agents for cardiovascular diseases

  • J Med Chem. 2008 Nov 13;51(21):6631-4. doi: 10.1021/jm8005096.
Clark A Sehon  1 ,  Gren Z Wang ,  Andrew Q Viet ,  Krista B Goodman ,  Sarah E Dowdell ,  Patricia A Elkins ,  Simon F Semus ,  Christopher Evans ,  Larry J Jolivette ,  Robert B Kirkpatrick ,  Edward Dul ,  Sanjay S Khandekar ,  Tracey Yi ,  Lois L Wright ,  Gary K Smith ,  David J Behm ,  Ross Bentley ,  Christopher P Doe ,  Erding Hu ,  Dennis Lee
Affiliations
  • 1. Departments of Medicinal Chemistry, Investigative Biology, Vascular Biology, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. [email protected]
PMID: 18842034 DOI: 10.1021/jm8005096
Abstract

Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and Molecular Biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.

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