2,3,5-Trisubstituted pyridines as selective AKT inhibitors-Part I: Substitution at 2-position of the core pyridine for ROCK1 selectivity

Bioorg Med Chem Lett. 2010 Jan 15;20(2):673-8. doi: 10.1016/j.bmcl.2009.11.064. Epub 2009 Nov 20.

Abstract

2,3,5-Trisubstituted pyridines have been designed as potent AKT inhibitors that are selective against ROCK1 based on the comparison between AKT and ROCK1 structures. Substitution at the 2-position of the core pyridine is the key element to provide selectivity against ROCK1. An X-ray co-crystal structure of 9p in PKA supports the proposed rationale of ROCK1 selectivity.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Proto-Oncogene Proteins c-akt
  • ROCK1 protein, human
  • rho-Associated Kinases