Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4

Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.