INCB-3344

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、选择性的、口服生物可利用的 CCR2 拮抗剂，对 hCCR2 和 mCCR2 的 IC50 分别为 5.1 nM 和 9.5 nM。

A potent, selective and orally bioavailable CCR2 antagonist with IC50 of 5.1 nM and 9.5 nM for hCCR2 and mCCR2, respectively, in MCP-1 binding assay; show no significant activity for murine CCR1 and murine CCR5 (IC50>1 uM), and a panel of >50 ion channels, transporters, chemokine receptors and other selected GPCRs; inhibits macrophage influx in a mouse model of delayed-type hypersensitivity, significantly reduces disease in models of multiple sclerosis, and inflammatory arthritis.Rheumatoid Arthritis Preclinical(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.

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.

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.

INCB 3344 | INCB3344

GPCR/G Protein

Chemokine Receptor

Chemokine Receptor

Inflammation/Immunology

Rheumatoid Arthritis

1262238-11-8

577.592

C29H34F3N3O6

>98% (HPLC)

10 mM in DMSO

CCOC1CN(CC1NC(=O)CNC(=O)C2=CC(=CC=C2)C(F)(F)F)C3CCC(CC3)(C4=CC5=C(C=C4)OCO5)O

Benzamide, N-[2-[[(3R,4R)-1-[trans-4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxy-3-pyrrolidinyl]amino]-2-oxoethyl]-3-(trifluoromethyl)-, rel-

(-20℃)

With Ice Pack

≥ 2 years