Discovery of Novel Non-Peptide CCR1 Receptor Antagonists

• Published in: Journal of medicinal chemistry 1999-11, Vol.42 (22), p.4680-4694
• Main Authors: Ng, Howard P, May, Karen, Bauman, John G, Ghannam, Ameen, Islam, Imadul, Liang, Meina, Horuk, Richard, Hesselgesser, Joseph, Snider, R. Michael, Perez, H. Daniel, Morrissey, Michael M
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Calcium - metabolism; Cell Line; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5 - metabolism; Drug Evaluation, Preclinical; Humans; Macrophage Inflammatory Proteins - metabolism; Macrophage Inflammatory Proteins - pharmacology; Medical sciences; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - metabolism; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Receptors, CCR1; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990316l

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 1 was optimized synthetically to the highly potent receptor antagonist 6s. 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 6s 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 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.