A novel CC chemokine receptor 4 antagonist RS-1269 inhibits ovalbumin-induced ear swelling and lipopolysaccharide-induced endotoxic shock in mice.
A novel CC chemokine receptor 4 antagonist RS-1269 inhibits ovalbumin-induced ear swelling and lipopolysaccharide-induced endotoxic shock in mice.
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一种新型 CC 趋化因子受体 4 拮抗剂 RS-1269 可抑制卵清蛋白诱导的小鼠耳肿胀和脂多糖诱导的内毒素休克。
DOI：
10.1111/j.1742-7843.2010.00578.x
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发表时间：
2010
影响因子：
3.1
通讯作者：
M. Yamashita
中科院分区：
文献类型：
--
作者：
Y. Nakagami;Kayo Kawashima;Maki Etori;K. Yonekubo;Chie Suzuki;Takaaki Jojima;Takeshi Kuribayashi;F. Nara;M. Yamashita
越来越多的证据表明，趋化因子在过敏、炎症和免疫反应中招募白细胞。CC趋化因子受体4 （CCR4）是辅助性T 2细胞的优先标记物，细胞选择性地响应CC趋化因子配体17 （CCL17）和CCL22。我们从内部文库中寻找具有CCR4拮抗剂特征的化合物，并先前报道了3-{2-[(2R)-2-苯基-4-（4-吡啶-4-基苄基）morpholin-2-yl]乙基}喹唑啉-2,4(1H,3H)-二酮（命名为RS-1154）能够显著抑制[(125)I]CCL17与表达CCR4的人CHO细胞的结合。在其衍生物的进一步合成中，我们重点研究了3-（异丁基氨基）- n- {2-[(2R)-2-苯基-4-（4-吡啶-4-基苄基）morpholin-2-yl]乙基}苯酰胺（RS-1269），其在体外抑制ccl17诱导的DO11.10小鼠源性T辅助2细胞迁移的效价与RS-1154相当，IC（50）值为5.5 nM。然后，我们研究了RS-1269对卵清蛋白诱导的小鼠耳肿胀和脂多糖诱导的内毒素休克的药理作用。以30mg /kg剂量口服RS-1269可显著降低大鼠耳厚。脂多糖治疗可显著提高血清肿瘤坏死因子-α水平。与抗ccl17抗体相比，RS-1269在100 mg/kg剂量下显著抑制ccl17的产生。这些结果提高了RS-1269或其衍生物之一有潜力作为开发特应性皮炎和炎症性疾病治疗剂的原型化合物的可能性。
There is growing evidence that chemokines recruit leukocytes in allergic, inflammatory and immune responses. CC chemokine receptor 4 (CCR4) is implicated as a preferential marker for T helper 2 cells, and the cells selectively respond to CC chemokine ligand 17 (CCL17) and CCL22. We searched for compounds having a profile as a CCR4 antagonist from an in-house library and have previously reported that 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154) was capable of significantly inhibiting the binding of [(125) I]CCL17 to human CCR4-expressing CHO cells. From further synthesis of its derivatives, we newly focused on 3-(isobutyrylamino)-N-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}benzamide (RS-1269), which showed potency comparable to RS-1154 in inhibiting CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 5.5 nM in vitro. We then investigated the pharmacological effects of RS-1269 on ovalbumin-induced ear swelling and lipopolysaccharide-induced endotoxic shock in mice. The ear thickness was significantly decreased by oral administration of RS-1269 at the dose of 30 mg/kg. Treatment with lipopolysaccharide significantly increased the serum level of tumour necrosis factor-α. Compared with an anti-CCL17 antibody, RS-1269 significantly inhibited the production at the dose of 100 mg/kg. These results raise the possibility that RS-1269 or one of its derivatives has potential to serve as a prototype compound to develop therapeutic agents for atopic dermatitis and inflammatory diseases.
Interleukin-4 诱导特应性皮炎患者 B 细胞分泌 IgE 和 IgG4。
DOI：
10.1159/000235357
发表时间：
1991
期刊：
International archives of allergy and applied immunology
影响因子：
--
作者：
Spiegelberg,HL;O'Connor,RD;Falkoff,RJ;Beck,L
通讯作者：
Beck,L