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.
Merck Research Laboratories, 2015 Galloping Hill Road Kenilworth, NJ, 07033, USA. michael.dwyer@spcorp.com
Michael P
MP
Dwyer
Purakattle
P
Biju
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