Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokinereceptor-2 ( CCR2): compounds with polar C3 side chains exhibited good ion channelselectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailabilityin preclinical species but poor ion channelselectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface areaand higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.