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新型γ-氨基丁酸（GABA）摄取抑制剂的合成。1. 结构-活性研究的阐释，该研究促使选择(R)-1-[4,4-双(3-甲基-2-噻吩基)-3-丁烯基]-3-哌啶甲酸（噻加宾）作为抗惊厥药物候选物。

The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate.

作者信息

Andersen K E, Braestrup C, Grønwald F C, Jørgensen A S, Nielsen E B, Sonnewald U, Sørensen P O, Suzdak P D, Knutsen L J

机构信息

Pharmaceuticals Division, Novo Nordisk A/S, Måløv, Denmark.

出版信息

J Med Chem. 1993 Jun 11;36(12):1716-25. doi: 10.1021/jm00064a005.

DOI:10.1021/jm00064a005
PMID:8510100
Abstract

A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.

摘要

本文描述了一系列用于合成新型GABA摄取抑制剂的不同方法，得到了一些化合物实例，它们是哌啶酸和四氢烟酸的衍生物，其氮原子上被4,4-二芳基-3-丁烯基或2-(二苯基甲氧基)乙基部分取代。测定了每种化合物对大鼠突触体中[3H]-GABA摄取的体外抑制值。结果发现，活性最强的实例是那些在一个或两个芳族/杂芳族基团的“邻位”具有取代基的化合物。所描述的大多数化合物在结构上与噻加宾，(R)-1-[4,4-双(3-甲基-2-噻吩基)-3-丁烯基]-3-哌啶羧酸盐酸盐(NNC 05-0328)相关，并总结了选择该化合物作为候选药物的一些理由。

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The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate.新型γ-氨基丁酸（GABA）摄取抑制剂的合成。1. 结构-活性研究的阐释，该研究促使选择(R)-1-[4,4-双(3-甲基-2-噻吩基)-3-丁烯基]-3-哌啶甲酸（噻加宾）作为抗惊厥药物候选物。
J Med Chem. 1993 Jun 11;36(12):1716-25. doi: 10.1021/jm00064a005.
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