Synthesis and biological evaluation of phenyl piperidine derivatives as CCR2 antagonists

A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure–activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.

Graphical abstractA series of phenyl piperidine derivatives have been synthesized and evaluated as CCR2 antagonists.Figure optionsDownload full-size imageDownload as PowerPoint slide