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

[1] Synthesis of (R)-1-(4-[C-11]-p-methoxyphenyl-4-phenyl-3-butenyl)-3-piperidinecarboxylic acid for positron emission tomography of the GABA uptake carrier
Vandersteene, I
Slegers, G
APPLIED RADIATION AND ISOTOPES, 1996, 47 (02) : 201 - 205
[2] (R)-N-[4,4-BIS(3-METHYL-2-THIENYL)BUT-3-EN-1-YL]NIPECOTIC ACID BINDS WITH HIGH-AFFINITY TO THE BRAIN GAMMA-AMINOBUTYRIC ACID UPTAKE CARRIER
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NIELSEN, EB
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ANDERSEN, KE
JANSEN, JA
FREDERIKSEN, K
ANDERSEN, PH
MORTENSEN, A
SUZDAK, PD
JOURNAL OF NEUROCHEMISTRY, 1990, 54 (02) : 639 - 647
[3] Synthesis of 4,4-bis(2-methylphenyl)-3-butenyl (and butyl) analogs of 4-phenyl-1,4- and 6-phenyl-1,6-dihydropyridine-3-carboxylic acids and their evaluation as neuronal GABA-uptake inhibitors
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Wei, ZY
Baker, GB
Knaus, EE
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[4] Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic
Huang, Huoming
Li, Xueping
Xie, Peng
Li, Xinwei
Xu, XueJun
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Yuan, Congmin
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Alagarsamy, V
Sulthana, M. T.
Chitra, K.
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[6] Structure-activity relationship studies of novel 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: Synthesis and biological evaluation at the dopamine and serotonin transporter sites
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Xu, C
Reith, MEA
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Hatzelmann, A
Van der Laan, IJ
Sterk, GJ
Thibaut, U
Timmerman, H
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