Monocyte chemo-attractant protein (MCP-1/CCL2) is a CC chemokine and binds to chemokine receptor 2 (CCR2), which is expressed on the majority of blood born monocytes.  CCR2 antagonism has been suggested as a viable approach for the treatment of a variety of inflammatory and autoimmune diseases including rheumatoid arthritis, multiple sclerosis and atherosclerosis.  We describe herein a novel series of 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists. A divergent SAR studies on hCCR2 and hERG activities led to the discovery of a lead compound as potent CCR2 antagonist with low nM affinity for CCR2 on human monocytes and low nM in the chemotaxis assay.  Moreover, it exhibited high selectivity for CCR2 over hERG and had a clean CV safety profile as evaluated in guinea pigs and dogs. It also had amendable oral bioavailability in preclinical species and demonstrated efficacy in multiple animal models. Detailed SAR, in vivo proof of concept studies as well as other preclinical properties of the lead compound will be discussed.

Discovery of a novel CCR2 antagonist as development candidate via divergent SARs of CCR2 and hERG

244th National Meeting (2012)

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