Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.

Compounds such as 5j (IC50 = 0.11 nM) are potent inhibitors of VLA-4.Figure optionsDownload as PowerPoint slide