Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists

CCR6 is a chemokine receptor that mediates the migration
of pathogenic
inflammatory leukocytes to sites of inflammation in response to its
ligand, CCL20. Herein we report the design of a potent CCR6 antagonist
capable of inhibiting the chemotactic migration of CCR6+ T cells in vitro. Key to this finding was the discovery of a remarkable
methyl substituent effect on antagonist potency. A 365-fold improvement
in potency was observed for the cis-2-methylcyclohexanamine
analogue compared to the unsubstituted cyclohexanamine derivative.
Evidence generated through the characterization of conformationally
restricted analogues supports the conclusion that the large potency
enhancement is the result of the methyl substituent biasing the cyclohexane
ring ground state conformation to favor that of the bound ligand and
thus decreasing the ligand strain energy.