Highly constrained bicyclic VLA-4 antagonists

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic β-amino acids (β-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (ϕ) between the amino and the carboxyl termini of the β-aa. Compound 5m where the β-aa is embedded in a bicycle possesses the most preferred ϕ (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig α4β1 IC50 = 54 nM, rat po F = 49%).

VLA-4 antagonists containing a bicyclic β-amino acid were studied. Activity was found to be related to the P3-amino-carboxy dihedral angle in the bicycle. The best compound, 5m, had VLA-4 IC50 of 54 nM and a 49% bioavailability in the rat at 2 mpk.Figure optionsDownload as PowerPoint slide