4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors

Bioorg Med Chem Lett. 2009 Sep 1;19(17):5191-4. doi: 10.1016/j.bmcl.2009.07.022. Epub 2009 Jul 9.

Abstract

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / chemistry
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / metabolism
  • Drug Design
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • Benzimidazoles
  • Oxadiazoles
  • Protein Kinase Inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Glycogen Synthase Kinase 3