Discovery of 3,4-diaminocyclobut-3-ene-1,2-dione-based CXCR2 receptor antagonists for the treatment of inflammatory disorders
- PMID: 20536426
- DOI: 10.2174/156802610791561246
Discovery of 3,4-diaminocyclobut-3-ene-1,2-dione-based CXCR2 receptor antagonists for the treatment of inflammatory disorders
Abstract
The CXC chemokine receptor 2 (CXCR2) has attracted a considerable amount of attention as a target for therapeutic intervention due the key role this receptor plays in a number of inflammatory disorders. Over the past decade, several classes of potent, selective CXCR2 receptor antagonists have been developed as potential anti-inflammatory agents. These small-molecule chemokine receptor antagonists have demonstrated the ability to inhibit CXCR2-mediated recruitment of inflammatory cells in-vitro as well as shown efficacy in-vivo in various animal models of inflammation. In addition, several of the most advanced CXCR2 receptor antagonists have recently demonstrated promising proof-of-activity results in early human clinical trials. This review details the discovery and development of the 3,4-diaminocyclobut-3-ene-1,2-dione-based CXCR2 receptor antagonist class including SCH 527123 which is currently in mid-stage clinical evaluation. The medicinal chemistry efforts leading to the discovery of SCH 527123, the in-vitro and in-vivo pharmacology for this compound, and an overview of the clinical evaluation of SCH 527123 will also be discussed.
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