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Combinatorial chemistry techniques applied to nonpeptide integrin antagonists

W J Hoekstra¹, B L Poulter

¹Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Rds., Spring House, Pennsylvania 19477, USA.

Current Medicinal Chemistry

|July 1, 1998

Summary

Nonpeptide integrin antagonists, designed using the RGD sequence, show promise for treating thrombosis, cancer, and osteoporosis. Combinatorial synthesis rapidly optimizes these drug leads for improved efficacy.

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Area of Science:

Biochemistry
Pharmacology
Drug Discovery

Background:

Integrins are cell surface receptors binding extracellular matrix proteins.
Nonpeptide integrin antagonists, based on the RGD sequence, are effective antithrombotics.
These antagonists also show therapeutic potential for cancer and osteoporosis.

Purpose of the Study:

To review progress in lead optimization of integrin antagonists.
Highlight drug design strategies and synthetic tactics for improved antagonists.
Focus on combinatorial synthesis approaches.

Main Methods:

Utilized combinatorial organic syntheses to create chemical mini-libraries.
Applied lead optimization strategies for nonpeptide integrin antagonists.

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Focused on RGD-mimicking structures.

Main Results:

Achieved marked success in nonpeptide lead optimization.
Demonstrated efficacy for antithrombotic agents (GPIIb/IIIa antagonists).
Benefited vitronectin receptor (avb3) antagonist research.

Conclusions:

Combinatorial synthesis is a powerful tool for developing integrin antagonists.
Drug design strategies have led to improved therapeutic candidates.
Integrin antagonists hold significant promise for multiple diseases.