Discovery of 3,5-bis(trifluoromethyl)benzyl l-arylglycinamide based potent CCR2 antagonists

Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50 = 30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50 = 50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.

Graphical abstractExtensive SAR of a screening hit resulted in a new series of potent and selective CCR2 receptor antagonists.Figure optionsDownload full-size imageDownload as PowerPoint slide