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学科主题: 生命有机化学
题名: Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent
其他题名: 1,3,3,4-四取代的吡咯烷CCR5受体的类似物的合成和生物评价。发现一种潜在的可口服生物利用的抗艾滋病毒剂
作者: Ma DW(马大为) ; Li B(李本) ; Chen L(陈力) ; Chen RH(陈仁海) ; Yu KQ(余昆前) ; Zhang LQ(张林奇) ; Chen ZW(陈志伟) ; Zhong DF(钟大放) ; Jiang HL(蒋华良) ; Wang RX(王任小) ; Pei G(裴刚)
通讯作者: 马大为
刊名: ChemMedChem
发表日期: 2007
卷: 2, 期:2, 页:187-193
收录类别: SCI
部门归属: 上海有机所; 上海生科院; 武汉大学; 沈阳药科; 药物所;
英文摘要: A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and subsequent 1,4-addition of benzylamine, in the key steps. These compounds bearing 4-(N,N-disubstituted)amino piperidine units showed low nanomolor potency against the CCR5 receptor, whereas molecules with a 4-phenylpiperidine moiety displayed poor activity. Asymmetric synthesis of the most potent compound 23 a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC50 values of 2.9 and 385.9 nm, respectively. These results indicated that (3 R,4S)-configuration in the series of compounds is favored for their interaction with the CCR5 receptor. The possible binding mode of these antagonists with the CCR5 receptor was discussed using a computer-modeling method. Compound 30 displayed excellent replication inhibition of seven genetically diverse R5 HIV-1 strains in the PBMC model, in a concentration-dependent manner with EC50 values ranging from 0.3 nm to 30 nm. This molecule showed oral bioavailabilities of 41.2% and 27.6% in rats and dogs, respectively. Thus, compound 30 is a promising candidate for the treatment of HIV-1 infection.
语种: 英语
相关网址: 查看原文
WOS记录号: WOS:000202946700006
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/15551
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
Ma DW,Li B,Chen L,et al. Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent[J]. ChemMedChem,2007,2(2):187-193.
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