Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1741-3. doi: 10.1016/j.bmcl.2011.01.075. Epub 2011 Jan 22.

Abstract

A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.

MeSH terms

  • Administration, Oral
  • Animals
  • Asthma / drug therapy*
  • Asthma / metabolism
  • Biological Availability
  • Disease Models, Animal*
  • Drug Discovery
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Sheep

Substances

  • Integrin alpha4beta1
  • Pyrimidines