The CC chemokine receptor 2 (CCR2) and its primary ligand, monocyte chemoattractant protein-1 (MCP-1), play key roles in attracting monocytes to sites of inflammation.  Inhibiting this receptor could impart beneficial outcomes in many disease states. We discovered an azetidinyl cyclohexane bis-amide scaffold bearing two consecutive amide bonds as potent CCR2 antagonists with good selectivity versus hERG. However, this type of functionality is prone to rapid metabolism in vivo, which might lead to low exposure. We describe herein our exploration on amide replacement by 5-membered heterocycle into 5/6-fused ring system such as indazole or benzoisoxazole to afford a novel series of CCR2 antagonists. Optimization of this series according to divergent SARs on both CCR2 and hERG generated a lead compound with potent CCR2 activity and good selectivity over hERG. Furthermore, the PK profile proved to be amenable with moderate clearance and volume distribution and high oral bioavailability in dogs, which is suitable for further development.

Discovery of indazole and benzoisoxazole containing 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists

244th National Meeting (2012)

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