The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

Directed screening of a carboxylic acid-containing combinatorial library le d to the discovery of potent inhibitors of the integrin VLA-4. Subsequent o ptimization by solid-phase synthesis afforded a series of sulfonylated dipe ptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chem istry. Preliminary metabolic studies led to the discovery of substituted bi phenyl derivatives with low picomolar activities. SAR and pharmacokinetic c haracterization of this series are presented. (C) 2001 Elsevier Science Ltd . All rights reserved.