Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2

Rational design based on a pharmacophore of CCR2 antagonists reported in the literature identified lead compound 9a with potent inhibitory activity against human CCR2 (hCCR2) but moderate activity against murine CCR2 (mCCR2). Modification on 9a led to the discovery of a potent CCR2 antagonist 21 (INCB3344) with IC50 values of 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonism and 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity. INCB3344 exhibited >100-fold selectivity over other homologous chemokine receptors, a free fraction of 24% in human serum and 15% in mouse serum, and an oral bioavailability of 47% in mice, suitable as a tool compound for target validation in rodent models.

Graphical abstractWe report the discovery of a novel series of CCR2 antagonists through rational design based on a pharmacophore reported in the literature. SAR studies led to the identification of a potent human and murine CCR2 antagonist INCB3344 with high selectivity and good oral bioavailability in mice.Figure optionsDownload full-size imageDownload as PowerPoint slide