Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis.

A series of novel, potent CCR1 inhibitors Was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR; data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained reveled the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred. in the center of the molecule; (3): substitutions. at the N-terminus are generally well tolerated. These data Were used to drive the optimization of the series; ultimately providing a lead with a CCR1 binding IC50 of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.