Chemotactic cytokine receptor-1 (CCR1) is a G protein-coupled receptor that belongs to a family of more than 20 chemokine receptors that have emerged as attractive targets for drug discovery. There are various chemokines that interact with these chemokine receptors and are well known to mediate basal and inflammatory leukocyte trafficking. CCR1 is expressed on immune cell types including monocytes, macrophages, T-lymphocytes, neutrophils, basophils, eosinophils, NK cells, mast cells and dendritic cells. The binding of the chemokine MIP-1 alpha (CCL3), MCP3 (CCL7) and RANTES (CCL5) to CCR1 is reported to play a role in the trafficking of monocytes, macrophages and Th1 cells to inflamed tissues in rheumatoid arthritis (RA) and multiple sclerosis (MS). Macrophages and Th1 cells in the synovia of RA patients are also major producers of MIP-1 alpha and RANTES, and they continuously recruit leukocytes to the synovial tissues of RA patients resulting in chronic inflammation. Thus, CCR1 has been regarded as a potential target for treating inflammatory disease. Antagonists that block the interactions between CCR1 and its chemokine ligands could block chemotaxis of monocytes, macrophages and Th1 cells to inflamed tissues ameliorating the chronic inflammation associated with autoimmune diseases such as RA and MS. However, in 2013, it was demonstrated by BMS that with sufficiently target coverage no significant efficacy was achieved in a Phase IIa RA trial. Consequently, development of BI 639667 was halted also.

Complex of human CCR2 with orthosteric and allosteric antagonists (PDB code: 5t1a)