946581-72-2Relevant articles and documents
Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis
Cavallaro, Cullen L.,Briceno, Stephanie,Chen, Jing,Cvijic, Mary Ellen,Davies, Paul,Hynes, John,Liu, Rui-Qin,Mandlekar, Sandhya,Rose, Anne V.,Tebben, Andrew J.,Van Kirk, Katy,Watson, Andrew,Wu, Hong,Yang, Guchen,Carter, Percy H.
supporting information, p. 9643 - 9653 (2013/01/16)
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 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.
