Discovery of 3,4-diaminocyclobut-3-ene-1,2-dione-based CXCR2 receptor antagonists for the treatment of inflammatory disorders.
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.
Dwyer
Michael P
MP
Merck Research Laboratories, 2015 Galloping Hill Road Kenilworth, NJ, 07033, USA. michael.dwyer@spcorp.com
Biju
Purakattle
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D003503:Cyclobutanes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008968:Molecular Conformation; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
C554998:3,4-diaminocyclobut-3-ene-1,2-dione; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003503:Cyclobutanes; D054390:Receptors, CCR2