Novel triazolopyridylbenzamides as potent and selective p38α inhibitors

Bioorg Med Chem Lett. 2012 May 15;22(10):3431-6. doi: 10.1016/j.bmcl.2012.03.099. Epub 2012 Apr 4.

Abstract

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.

MeSH terms

  • Benzamides / pharmacology*
  • Crystallography, X-Ray
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Models, Molecular
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 14