设计并合成了一系列吡啶并[2,3-d]嘧啶衍生物作为 CCR4 拮抗剂。
Design and synthesis of a series of pyrido[2,3-d]pyrimidine derivatives as CCR4 antagonists.
机构信息
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
出版信息
Molecules. 2012 Aug 20;17(8):9961-70. doi: 10.3390/molecules17089961.
A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD₅₀ of compound 6b is 175 mg/kg and the oral LD₅₀ is greater than 2,000 mg/kg.
基于已知的 CC 趋化因子受体 4（CCR4）拮抗剂，设计和合成了一系列吡啶并[2,3-d]嘧啶衍生物。所有新合成化合物的活性均通过趋化抑制测定进行评估。化合物 6b 被证明是一种有效的 CCR4 拮抗剂，可阻断巨噬细胞衍生趋化因子（MDC）、胸腺激活调节趋化因子（TARC）和 CCR4 的天然配体 CKLF1 诱导的细胞趋化。此外，化合物 6b 在小鼠鼻炎模型中的效果优于布地奈德。化合物 6b 的静脉注射 LD₅₀ 为 175mg/kg，口服 LD₅₀ 大于 2000mg/kg。
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