2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor

Bioorg Med Chem Lett. 2009 Feb 1;19(3):908-11. doi: 10.1016/j.bmcl.2008.11.105. Epub 2008 Dec 6.

Abstract

The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray
  • Cyclin A / chemistry
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Design
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Protein Isoforms
  • Protein Kinase C / chemistry*
  • Protein Kinase C / isolation & purification*

Substances

  • Benzimidazoles
  • Cyclin A
  • Enzyme Inhibitors
  • Imidazoles
  • Protein Isoforms
  • benzimidazole
  • protein kinase C zeta
  • Protein Kinase C
  • Cyclin-Dependent Kinase 2