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

被引：138

作者：

ANDERSEN, KE ^{[1
]}

BRAESTRUP, C ^{[1
]}

GRONWALD, FC ^{[1
]}

JORGENSEN, AS ^{[1
]}

NIELSEN, EB ^{[1
]}

SONNEWALD, U ^{[1
]}

SORENSEN, PO ^{[1
]}

SUZDAK, PD ^{[1
]}

KNUTSEN, LJS ^{[1
]}

机构：

[1] NOVO NORDISK AS,DIV PHARMACEUT,NOVO NORDISK PK,DK-2760 MALOV,DENMARK

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 12期

关键词：

D O I：

10.1021/jm00064a005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 [H-3]-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.

引用

页码：1716 / 1725

页数：10

共 24 条

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