2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: Synthesis and selectivity

Linear unselective CCR3 antagonist leads with IC50 values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3-acetylphenyl)urea exhibited single digit nanomolar IC50 values for CCR3 with >100-fold selectivity against an extensive counter screen panel.

Graphical abstractLinear unselective CCR3 antagonist leads with IC50 values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3-acetylphenyl)urea exhibited single digit nanomolar IC50 values for CCR3 with >100-fold selectivity against an extensive counter screen panel.Figure optionsDownload full-size imageDownload as PowerPoint slide