Discovery of a novel series of potent MK2 non-ATP competitive inhibitors using 1,2-substituted azoles as cis-amide isosteres

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3609-13. doi: 10.1016/j.bmcl.2014.05.024. Epub 2014 May 16.

Abstract

A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.

Keywords: Amide bond isostere; Conformational constraint; Ligand efficiency; MK2 inhibitors; cis-Amide bond.

MeSH terms

  • Amides / chemistry*
  • Animals
  • Azoles / chemical synthesis
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Molecular Conformation
  • Permeability / drug effects
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • Amides
  • Azoles
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases