Document Report Card

ID: ALA2176935

Journal: J Med Chem

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

Authors: Cavallaro CL, Briceno S, Chen J, Cvijic ME, Davies P, Hynes J, Liu RQ, Mandlekar S, Rose AV, Tebben AJ, Van Kirk K, Watson A, Wu H, Yang G, Carter PH.

Abstract: 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 revealed 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 IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.

CiteXplore: 23075267

DOI: 10.1021/jm300896d