Structure-Activity Relationships of Amino Acid-Containing lntegrin Antagonists

Interest in the development of specific antagonists of the 3 family of integrins {platelet aub3 and the vitronectin receptor av3 ) has been principally driven by efforts to design more potent antithrombotic agents than either aspirin or the thienopyridine-type ADP receptor modulators. The platelet fibrinogen receptor (aub3) and the vitronectin receptor (av 3) bind the RGD tripeptide sequence found within adhesive ligands. Because of this, many approaches to antagonists of 3 receptors have utilized an RGD mimetic to identify antagonists. lntegrin antagonists of many structurally diverse classes have been discovered. One of the larger 3 integrin antagonist classes employs -amino acids to mimic the aspartate residue of the RGD mimetic. Structure-activity investigations have revealed the potent activity of agents which have substituents appended to both the a and position of the -amino acid units of these antagonists. Several clinical candidates targeting platelet a11 b3 contain these -amino acid units and are currently being evaluated clinically.