3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase

J Med Chem. 2008 Oct 23;51(20):6280-92. doi: 10.1021/jm8005405. Epub 2008 Sep 26.

Abstract

The p38 mitogen-activated protein kinase (MAPK) is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.

MeSH terms

  • Administration, Oral
  • Amines / chemistry*
  • Animals
  • Arthritis / chemically induced
  • Arthritis / drug therapy
  • Arthritis / enzymology
  • Benzene / chemistry*
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Humans
  • Isoxazoles / administration & dosage*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Isoxazoles / therapeutic use
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / chemistry
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Phthalazines / chemistry*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Amines
  • Isoxazoles
  • Phthalazines
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 14
  • Benzene

Associated data

  • PDB/3DS6