Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase

Bioorg Med Chem Lett. 2003 Jan 20;13(2):277-80. doi: 10.1016/s0960-894x(02)00752-7.

Abstract

The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).

MeSH terms

  • Animals
  • Area Under Curve
  • Biological Availability
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • In Vitro Techniques
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Conformation
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Quinazolines
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases