10 research outputs found
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
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<sub>50</sub> of 28 nM (<b>48</b>). This lead demonstrates high selectivity for CCR1 over
other CCR-family members, high microsomal stability, and good pharmacokinetics
in mice