Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7107-12. doi: 10.1016/j.bmcl.2011.09.083. Epub 2011 Sep 24.

Abstract

Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC(50)=1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.

MeSH terms

  • Binding Sites
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • rho-Associated Kinases / antagonists & inhibitors*

Substances

  • 7-azaindole dimer
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Indoles
  • rho-Associated Kinases