title: Combinatorial chemistry techniques applied to nonpeptide integrin antagonists.
abstract: 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 antagonists designed after the adhesion recognition sequence RGD (Arg-Gly-Asp) not only have displayed efficacy as antithrombotic agents, but also have promise for the treatment of cancer and osteoporosis. Combinatorial organic syntheses of chemical mini-libraries have facilitated nonpeptide lead optimization of integrin antagonists with marked success. Although these accomplishments have been realized primarily for the discovery of orally active GPIIb/IIIa antagonist antithrombotics, vitronectin receptor (avb3) antagonist research has also benefited from such rapid synthesis. The purpose of this review is to report progress in combinatorial synthesis lead optimization by highlighting the drug design strategies and synthetic tactics that have led to improved integrin antagonists.
authors.affiliation: Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Rds., Spring House, Pennsylvania 19477, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: B L
authors.initials: BL
authors.lastname: Poulter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D018716:Molecular Mimicry; D010024:Osteoporosis / Q000188:drug therapy; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D005343:Fibrinolytic Agents; D039041:Integrin alpha4beta1; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016201:Receptors, Lymphocyte Homing; D019030:Receptors, Vitronectin