Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase

J Med Chem. 2011 Apr 14;54(7):2255-65. doi: 10.1021/jm101423y. Epub 2011 Mar 4.

Abstract

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

MeSH terms

  • Administration, Oral
  • Arthritis, Rheumatoid / drug therapy
  • Biological Availability
  • Cell Line
  • Clinical Trials as Topic
  • Drug Discovery / methods*
  • Humans
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / chemistry
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Pyridones / administration & dosage
  • Pyridones / chemistry
  • Pyridones / pharmacokinetics*
  • Pyridones / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido(2,3-d)pyrimidin-7(8H)-one
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidines
  • pamapimod
  • Mitogen-Activated Protein Kinase 14