Design, synthesis, and discovery of a novel CCR1 antagonist

The CC chemokines may play an important role in the pathogenesis of chronic inflammatory diseases including rheumatoid arthritis, and their effects ar e thought to be mediated through CCR1 receptors. Several nonpeptide CCR1 re ceptor antagonists that showed high affinity for human CCR1 receptors have been identified; however, their effectiveness in animal models of inflammat ory diseases has been scarcely demonstrated, probably due to species select ivity of the antagonists. To elucidate the pathophysiological role of CCR1 receptors in murine models of disease, we looked for a potent antagonist fo r both murine and human CCR1 receptors. Screening of our chemical collectio n for inhibition of I-125-MIP-1 alpha. binding to human CCR1 receptors tran sfected in CHO cells led to the identification of xanthene-9-carboxamide la as the lead compound. Derivatization of 1a by quaternarizing the piperidin e nitrogen with various alkyl groups and by installing substituents into th e xanthene moiety dramatically improved the inhibitory activity against bot h human and murine CCR1 receptors. As a result, 2q-1 showing IC50 values of 0.9 and 5.8 nM for human and murine CCR1 receptors, respectively, was disc overed. This compound is the first murine CCR1 receptor antagonist and may be a useful tool for clarifying the role of CCR1 receptors in murine models of disease.