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INCB3344

產(chǎn)品活性：INCB3344 是一種有效的 CCR2 拮抗劑，拮抗結(jié)合活性時(shí)，IC₅₀ 為 5.1 nM (hCCR2) 和 9.5 nM (mCCR2)，拮抗趨化活性時(shí)，IC₅₀ 為 3.8 nM (hCCR2) 和 7.8 nM (mCCR2)。

研究領(lǐng)域：GPCR/G Protein  |  Immunology/Inflammation

作用靶點(diǎn)：CCR

In Vitro: INCB3344 is a potent antagonist towards rat and cynomolgus CCR2 as well, displaying IC₅₀ values of 7.3 and 16 nM in binding antagonism and 2.7 and 6.2 nM in antagonism of chemotaxis activity, respectively. INCB3344 is a selective hCCR2 antagonist, exhibiting IC₅₀ values of more than 1 μM against a panel of >50 ion channels, transporters, chemokine receptors and other selected GPCRs. It is also a selective mCCR2 antagonist, showing IC₅₀ values of >1 μM and >3 μM against murine CCR1 and murine CCR5, respectively, the two most homologous chemokine receptors to mCCR2. Characterization of the pharmacological activity of INCB3344 is first evaluated by testing its ability to inhibit CCL2 binding to CCR2 in a whole cell binding assay using a murine monocyte cell line, WEHI-274.1 and ¹²⁵I-labeled mCCL2 as a tracer. The binding IC₅₀ of INCB3344 in this assay is determined to be 10±5 nM, and inhibition of >90% binding is observed at a concentration of 90 nM.

In Vivo: When administered intravenously to CD-1 mice, INCB3344 exhibits a high clearance and a moderate volume of distribution, resulting in a short half life of 1 h. Despite its high clearance, however, good oral exposure is achieved, with an AUC at 2664 nM h at a dose of 10 mg/kg. The oral bioavailability is 47%. By comparison, slightly better oral exposure (AUC=3888 nM h) is obtained when administered orally to Balb/c mice at the same dose. This PK property, couple with its potent anti-mCCR2 activity and good selectivity, makes this compound suitable for model studies in rodents. INCB3344 prevents Deoxycorticosterone acetate/salt-induced changes in vascular expression of CCR2. In a separate series of experiments, CCR2 expression is elevated (≈1.5-fold higher) in aortas from mice that receive INCB3344 from days 7 to 21 of the Deoxycorticosterone acetate/salt treatment period compare with sham animals; however, this level of CCR2 expression is significantly lower than that observed in the vehicle-treated group (P<0.05, n=6). Likewise, increased expression of its receptor ligand CCL2 in Deoxycorticosterone acetate/salt-treated mice is blunted in mice receiving INCB3344 (P<0.05, n=6). By contrast, levels of CCL7, CCL8, and CCL12 are elevated to similar extents in Deoxycorticosterone acetate/salt-treated mice receiving vehicle or INCB3344.

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