Potent antagonists of the CCR2b receptor. Part 3: SAR of the ( R)-3-aminopyrrolidine series

SAR studies of a 3-amino pyrrolidine series led to the identification of potent CCR2b antagonists with low nanomolar activity in binding and functional assays as exemplified by compound 71. SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC 50 3.2 nM; MCP-1-Induced Chemotaxis IC 50 0.83 nM; Ca 2+ Flux IC 50 7.5 nM].