INCB3344 is a potent, selective and orally bioavailableCCR2antagonist withIC₅₀values 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 is a potent antagonist towards rat and cynomolgus CCR2 as well, displaying IC₅₀values 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 IC₅₀values 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 IC₅₀values of >1 μM and >3 μM against murine CCR1 and murine CCR5, respectively, the two most homologous chemokine receptors to mCCR2^[1]. 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 and¹²⁵I-labeled mCCL2 as a tracer. The binding IC₅₀of INCB3344 in this assay is determined to be 10±5 nM, and inhibition of >90% binding is observed at a concentration of 90 nM^[2].

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^[1]. 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^[3].

577.59

Solid

C₂₉H₃₄F₃N₃O₆

1262238-11-8

Room temperature in continental US; may vary elsewhere.

DMSO : 220 mg/mL(380.89 mM;Need ultrasonic)

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• 1.

  请依序添加每种溶剂： 5% DMSO    95% (20%SBE-β-CDin saline)

  Solubility: 6 mg/mL (10.39 mM); Clear solution; Need ultrasonic
• 2.

  请依序添加每种溶剂： 5% DMSO    95%corn oil

  Solubility: 6 mg/mL (10.39 mM); Clear solution; Need ultrasonic
• 3.

  请依序添加每种溶剂： 5% DMSO    40%PEG300   5%Tween-80   50% saline

  Solubility: ≥ 2.75 mg/mL (4.76 mM); Clear solution