Capped diaminopropionamide–glycine dipeptides are inhibitors of CC chemokine receptor 2 (CCR2)

A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure–activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10–30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca2+ flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.

Graphical abstractA new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure–activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three substituents. Compound 54 exhibited potent activity (CCR2 binding IC50 = 19 nM; Chemotaxis IC50 = 39 nM) and good selectivity over CCR1 and CCR3.Figure optionsDownload full-size imageDownload as PowerPoint slide