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: W J Hoekstra, B L Poulter
• Journal: Current medicinal chemistry (Curr Med Chem) Vol. 5 Issue 3 Pg. 195-204 (Jun 1998) ISSN: 0929-8673 [Print] United Arab Emirates
• PMID: 9562602 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Fibrinolytic Agents
• Integrin alpha4beta1
• Integrins
• Platelet Glycoprotein GPIIb-IIIa Complex
• Receptors, Lymphocyte Homing
• Receptors, Vitronectin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Drug Design
• Fibrinolytic Agents (chemical synthesis, pharmacology, therapeutic use)
• Humans
• Integrin alpha4beta1
• Integrins (antagonists & inhibitors)
• Molecular Mimicry
• Osteoporosis (drug therapy)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Receptors, Lymphocyte Homing (antagonists & inhibitors)
• Receptors, Vitronectin (antagonists & inhibitors)