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

Reversal of Vascular Macrophage Accumulation and Hypertension by a CCR2 Antagonist in Deoxycorticosterone/Salt-Treated Mice

“…First, INCB3344 is equally effective at antagonizing the human CCR2 receptor as it is at antagonizing the rodent receptor, with binding affinities in the low nanomolar range. 7,8 Second, INCB3344 is highly selective (>100-fold) for CCR2 more than even the most closely related chemokine receptor subtypes, such as CCR1 and CCR5, 7 suggestive of limited off-target effects. Finally, INCB3344 was shown to have high oral bioavailability in mice (>45%).…”

“…Finally, INCB3344 was shown to have high oral bioavailability in mice (>45%). 7 It has been shown that the CCR2 ligand, CCL2 (formerly known as monocyte chemo-attractant protein-1), is upregulated in the vascular wall during experimental hypertension. 2,24 In the present study, we confirmed this finding and then showed for the first time that several additional CCR2 ligands are also upregulated in the vascular wall during DOCA/salt-induced hypertension, including CCL7 (MCP-3), CCL8 (MCP-2), and CCL12 (MCP-5).…”

“…After induction of hypertension (or sham treatment), systolic BP was measured via tail cuff plethysmography on days 0, 3,7,10,14,17, and 21 using the MC4000 Multichannel system (Hatteras Instruments).…”

“…5 In the present study, we performed a polymerase chain reaction (PCR) screen to identify chemokine receptor genes that are upregulated in the vascular wall of mice after induction of hypertension by treatment with a combination of deoxycorticosterone acetate (DOCA) and salt. Having identified CCR2 as one such chemokine receptor, we then examined the effect of a recently described and highly selective CCR2 antagonist, INCB3344, [7][8][9] on macrophage accumulation and blood pressure (BP) in the DOCA/salt model. Treatment of mice with INCB3344 reversed DOCA/ salt-induced increases in CCR2 expression and macrophage accumulation in the vascular wall.…”

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

“…4À10 We have reported the discovery of a novel series of CCR2 antagonists through rational design. 10 Our structureÀactivity relationship (SAR) studies on that series of compounds led to the identification of INCB3344 (Figure 1), a potent, selective, and orally bioavailable antagonist of human and murine CCR2 (hCCR2 and mCCR2). INCB3344 has been used as a tool compound for target validation in rodent models because of its potent inhibitory activity toward murine CCR2, its selectivity over other homologous chemokine receptors, and its good pharmacokinetics profile but was not suitable as a clinical candidate due to its moderate hERG activity (IC 50 = 13 μM) as assessed using a dofetilide binding assay, which did not meet our criteria in hERG binding activity.…”