Structure-activity relationships of beta-amino acid-containing integrin antagonists

Interest in the development of specific antagonists of the beta3 family of integrins (platelet alphaIIbbeta3 and the vitronectin receptor alphavbeta3) 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 (aIIbb3) and the vitronectin receptor (alphavbeta3) bind the RGD tripeptide sequence found within adhesive ligands. Because of this, many approaches to antagonists of beta3 receptors have utilized an RGD mimetic to identify antagonists. Integrin antagonists of many structurally diverse classes have been discovered. One of the larger beta3 integrin antagonist classes employs beta-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 alpha and beta position of the beta-amino acid units of these antagonists. Several clinical candidates targeting platelet aIIbb3 contain these beta-amino acid units and are currently being evaluated clinically.