1. Academic Validation
  2. Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors

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

Affiliation

  • 1 Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. [email protected]
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.

Figures
Products