Discovery of Novel Non-Peptide CCR1 Receptor Antagonists

Ligands for the CCR1 receptor (MIP-1α and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1α and RANTES to the recombinant human CCR1 chemokine receptor. The structure−activity relationships of various segments of this template are described as the initial HTS lead <BO>1 </BO>was optimized synthetically to the highly potent receptor antagonist <BO>6s</BO>. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound <BO>6s</BO> and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound <BO>6s</BO> potentially represent a novel approach to the treatment of chronic inflammatory diseases.