Pharmacological profile of JNJ-27141491 [(S)-3-[3,4-difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole4-carboxyl acid methyl ester], as a noncompetitive and orally active antagonist of the human chemokine receptor CCR2
Pharmacological profile of JNJ-27141491 [(S)-3-[3,4-difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole4-carboxyl acid methyl ester], as a noncompetitive and orally active antagonist of the human chemokine receptor CCR2
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DOI：
10.1124/jpet.108.140723
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发表时间：
2008-10-01
影响因子：
3.5
通讯作者：
Van Wauwe, Jean P.
中科院分区：
文献类型：
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作者：
Buntinx, Mieke;Hermans, Bart;Van Wauwe, Jean P.
CC趋化因子受体2（CCR 2）与单核细胞趋化蛋白（如MCP-1）之间的相互作用调节炎性白细胞的活化和募集。在本研究中，我们将（S）-3-[3，4-二氟-苯基）-丙基]5-异恶唑-5-基-2-硫代-2，3-二氢-1H-咪唑-4-羧酸甲酯（JNJ-27141491）表征为人（h）CCR 2的非竞争性口服活性功能性拮抗剂。JNJ-27141491强烈抑制hCCR 2介导的体外功能，如MCP-1诱导的鸟苷5 '-O-（3-[S-35]硫代）三磷酸结合; MCP-1、-3和-4诱导的Ca 2+动员;以及白细胞对MCP-1的趋化性（IC 50 = 7-97 nM），而对检测的其他趋化因子受体的功能影响很小或没有影响。CCR 2功能的抑制是不可克服的和可逆的，与非竞争性作用模式一致。JNJ-27141491阻断I-125-MCP-1与人单核细胞的结合（IC 50 = 0.4 μ M），但未能影响MCP-1与小鼠、大鼠和犬细胞的结合（IC 50> 10 μ M）。因此，产生了转基因小鼠，其中小鼠（m）CCR 2基因被人对应物取代，用于体内测试。在这些小鼠中，JNJ-27141491剂量依赖性经口给药[5-40 mg/kg q.d. (once每日）或每日两次]抑制单核细胞和中性粒细胞向肺泡腔的募集。此外，JNJ-27141491（20 mg/kg q.d.）在多发性硬化症的实验性自身免疫性脑脊髓炎模型中，综上所述，这些结果确定JNJ-27141491为hCCR 2的非竞争性功能性拮抗剂，能够在表达hCCR 2的转基因小鼠中发挥口服抗炎活性。
The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized (S)-3-[3,4-difluoro-phenyl)-propyl]5- isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4- carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h) CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5'-O-(3-[S-35] thio) triphosphate binding; MCP-1, -3, and -4-induced Ca2+ mobilization; and leukocyte chemotaxis toward MCP-1 (IC50 = 7-97 nM), whereas it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a noncompetitive mode of action. JNJ-27141491 blocked the binding of I-125-MCP-1 to human monocytes (IC50 = 0.4 mu M), but it failed to affect MCP-1 binding to mouse, rat, and dog cells (IC50 > 10 mu M). Therefore, transgenic mice, in which the mouse (m) CCR2 gene was replaced by the human counterpart, were generated for in vivo testing. In these mice, oral administration of JNJ-27141491 dose-dependently [5-40 mg/kg q.d. (once daily) or b.i.d.] inhibited monocyte and neutrophil recruitment to the alveolar space 48 h after intratracheal mMCP-1/lipopolysaccharide instillation. Furthermore, treatment with JNJ-27141491 (20 mg/kg q.d.) significantly delayed the onset and temporarily reduced neurological signs in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Taken together, these results identify JNJ-27141491 as a noncompetitive, functional antagonist of hCCR2, capable of exerting oral anti-inflammatory activity in transgenic hCCR2-expressing mice.