Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors

  • J Med Chem. 2007 Jan 11;50(1):6-9. doi: 10.1021/jm0609014.
Krista B Goodman  1 ,  Haifeng Cui ,  Sarah E Dowdell ,  Dimitri E Gaitanopoulos ,  Robert L Ivy ,  Clark A Sehon ,  Robert A Stavenger ,  Gren Z Wang ,  Andrew Q Viet ,  Weiwei Xu ,  Guosen Ye ,  Simon F Semus ,  Christopher Evans ,  Harvey E Fries ,  Larry J Jolivette ,  Robert B Kirkpatrick ,  Edward Dul ,  Sanjay S Khandekar ,  Tracey Yi ,  David K Jung ,  Lois L Wright ,  Gary K Smith ,  David J Behm ,  Ross Bentley ,  Christopher P Doe ,  Erding Hu ,  Dennis Lee
Affiliations
  • 1. Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. [email protected]
PMID: 17201405 DOI: 10.1021/jm0609014
Abstract

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 Inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

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