The search for CC Chemokine Receptor-2 (CCR2) antagonists has been complicated by challenges in balancing molecular properties. Our own studies in a series of trisubstituted cyclohexyl compounds confirmed this trend, and largely led to molecules that exhibited either poor oral bioavailability or poor ion channel selectivity. Our attempts to address this problem through simple modification of physicochemical properties failed. Ultimately, we were able to advance the series through the installation of a protonation-dependent conformational switching mechanism. Subsequent optimization enabled the identification of orally bioavailable CCR2 antagonists with good oral bioavailability and high ion channel selectivity. We will discuss these efforts in the context of the discovery of two molecules that advanced to human clinical studies.

Use of a pH-dependent conformational switching mechanism to enable the discovery of potent, selective and orally bioavailable CCR2 antagonists

2019 Spring National Meeting

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