Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4907-11. doi: 10.1016/j.bmcl.2012.04.104. Epub 2012 Apr 30.

Abstract

Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacology
  • Animals
  • Drug Evaluation, Preclinical
  • Hedgehog Proteins / antagonists & inhibitors*
  • Mice
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Structure-Activity Relationship

Substances

  • Amides
  • Hedgehog Proteins
  • Protein Kinase Inhibitors
  • Receptors, G-Protein-Coupled
  • Mitogen-Activated Protein Kinase 14