CCR2 Small Molecule Antagonists

The in vivo efficacy seen with anti-MCP-1 antibodies and peptide antagonists prompts the search for small molecule CCR2 antagonists. The spiropiperidines (18-20) are early examples of CCR2 antagonists, as determined by 125I-MCP-1 binding and chemotaxisin THP-1 cells (110).As noted above with the CCR1 antagonists, a basic nitrogen is a common feature within this class of antagonists. Site-di-mutagenesis suggests that this nitrogen may form a critical recognition with an anionic residue (E291) in helix 7. The orthogonal relationship imposed on the phenyurethane and the piperidine ring by the spiro-carbon is urported to be essential for activity.

Selectivity is an issue for the spiropiperi-dines, given that this class of compounds shows appreciable activity against alpha adrenergic and 5-hydroxytiyptamine (5-HT) receptors. Although lead optimization improved CCR2 affinity (18) versus (20), and improved the relative difference in selectivity, the most

(19)

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