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

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. A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagoni...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-03, Vol.21 (6), p.1741-1743
Hauptverfasser:	Semko, Christopher M., Chen, Linda, Dressen, Darren B., Dreyer, Mark L., Dunn, Whitney, Farouz, Francine S., Freedman, Stephen B., Holsztynska, Elizabeth J., Jefferies, Michael, Konradi, Andrei W., Liao, Anna, Lugar, Judevin, Mutter, Linda, Pleiss, Michael A., Quinn, Kevin P., Thompson, Thomas, Thorsett, Eugene D., Vandevert, Christopher, Xu, Ying-Zi, Yednock, Ted A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antagonist antagonists Asthma Asthma - drug therapy Asthma - metabolism Biological and medical sciences Biological Availability Bones, joints and connective tissue. Antiinflammatory agents chemistry Disease Models, Animal Drug Discovery Immunomodulators Integrin Integrin alpha4beta1 - antagonists & inhibitors Medical sciences Pharmacology. Drug treatments Pyrimidine Pyrimidines - pharmacokinetics Pyrimidines - therapeutic use Sheep VLA-4
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Zusammenfassung:	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. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.01.075