COMBINATORIAL CHEMISTRY TECHNIQUES APPLIED TO NONPEPTIDE INTEGRIN ANTAGONISTS

The integrins are cell surface receptors that recognize extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin, and VCAM-1 (vascular cell adhesion molecule-1). Nonpeptide integrin a ntagonists designed after the adhesion recognition sequence RGD (Arg-G ly-Asp) not only have displayed efficacy as antithrombotic agents, but also have promise for the treatment of cancer and osteoporosis. Combi natorial organic syntheses of chemical mini-libraries have facilitated nonpeptide lead optimization of integrin antagonists with marked succ ess. Although these accomplishments have been realized primarily for t he discovery of orally active GPIIb/IIIa antagonist antithrombotics, v itronectin receptor (alpha(v) beta(3)) antagonist research has also be nefited from such rapid synthesis. The purpose of this review is to re port progress in combinatorial synthesis lead optimization by highligh ting the drug design strategies and synthetic tactics that have led to improved integrin antagonists.