Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent
文献类型：期刊论文
| 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) |
| 刊名 | ChemMedChem
 |
| 出版日期 | 2007 |
| 卷号 | 2期号:2页码:187-193 |
| ISSN号 | 1860-7179 |
| 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 |
| 通讯作者 | 马大为 |
| 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. |
| 学科主题 | 生命有机化学 |
| 收录类别 | SCI |
| 原文出处 | http://dx.doi.org/10.1002/cmdc.200600182 |
| 语种 | 英语 |
| WOS记录号 | WOS:000202946700006 |
| 公开日期 | 2013-02-19 |
| 源URL | [http://202.127.28.38/handle/331003/15551]  |
| 专题 | 上海有机化学研究所_生命有机化学国家重点实验室 |
| 推荐引用方式 GB/T 7714 | 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. |
| APA | 马大为.,李本.,陈力.,陈仁海.,余昆前.,...&裴刚.(2007).Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.ChemMedChem,2(2),187-193. |
| MLA | 马大为,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".ChemMedChem 2.2(2007):187-193. |
入库方式： OAI收割
来源：上海有机化学研究所
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