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

Christopher M Semko; Linda Chen; Darren B Dressen; Mark L Dreyer; Whitney Dunn; Francine S Farouz; Stephen B Freedman; Elizabeth J Holsztynska; Michael Jefferies; Andrei W Konradi; Anna Liao; Judevin Lugar; Linda Mutter; Michael A Pleiss; Kevin P Quinn; Thomas Thompson; Eugene D Thorsett; Christopher Vandevert; Ying-Zi Xu; Ted A Yednock

doi:10.1016/j.bmcl.2011.01.075

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.

Affiliation

¹ Elan Pharmaceuticals, Inc., S. San Francisco, CA 94080, USA. [email protected]

PMID: 21316228
DOI: 10.1016/j.bmcl.2011.01.075

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