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

Interest in the development of specific antagonists of the beta(3) family o f integrins (platelet alpha(IIb)beta(3) and the vitronectin receptor (alpha (v)beta(3)) has been principally driven by efforts to design more potent an tithrombotic agents than either aspirin or the thienopyridine-type ADP rece ptor modulators. The platelet fibrinogen receptor (alpha(IIb)beta(3)) and t he vitronectin receptor (alpha(v)beta(3)) bind the RGD tripeptide sequence found within adhesive ligands. Because of this, many approaches to antagoni sts of beta(3) receptors have utilized an RGD mimetic to identify antagonis ts. Integrin antagonists of many structurally diverse classes have been dis covered. One of the larger beta(3) integrin antagonist classes employs beta -amino acids to mimic the aspartate residue of the RGD mimetic. Structure-a ctivity investigations have revealed the potent activity of agents which ha ve substituents appended to both the alpha and beta position of the beta-am ino acid units of these antagonists. Several clinical candidates targeting platelet alpha(IIb)beta(3) contain these beta-amino acid units and are curr ently being evaluated clinically.