Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase

J Med Chem. 2005 Sep 8;48(18):5728-37. doi: 10.1021/jm050346q.


Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Binding Sites
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Mimicry
  • Molecular Structure
  • Protein Binding
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Quantitative Structure-Activity Relationship
  • Static Electricity
  • Triazoles / chemical synthesis
  • Triazoles / chemistry*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry*


  • Benzimidazoles
  • Pyridines
  • Triazoles
  • benzimidazolone
  • p38 Mitogen-Activated Protein Kinases