Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors

被引：16

作者：

Sitka, Ingolf ^{[1
]}

Allmendinger, Lars ^{[1
]}

Fuelep, Guenther ^{[1
]}

Hoefner, Georg ^{[1
]}

Wanner, Klaus T. ^{[1
]}

机构：

[1] LMU Munchen, Dept Pharm, Zentrum Pharmaforsch, D-81377 Munich, Germany

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 65卷

关键词：

GABA uptake inhibitors; Antiepileptic; GAT1; BGT1; GAT2; GAT3; beta-amino acids; Mitsunobu reaction; HIGH-AFFINITY; TRANSPORTER; CLONING; EXPRESSION; POTENT; IDENTIFICATION; HETEROGENEITY; DERIVATIVES; SELECTIVITY; TIAGABINE;

D O I：

10.1016/j.ejmech.2013.04.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this publication, we describe the synthesis of new inhibitors for the GABA transporter subtypes GAT1 and especially GAT3. We started with 3-aminopropanoic acid possessing a distinct preference for GAT3 in comparison to GAT1 and furthermore its homolog 3-aminobutanoic acid. A series of respective N-substituted amino acids was synthesized by selective N-monoalkylation of these parent structures with 6 different arylalkyl alcohols via a Mitsunobu-type reaction. The resulting compounds were investigated for their inhibitory potency GABA transporter subtypes. Among all tested compounds the 4,4-diphenylbut-3-enyl substituted 3-aminobutanoic acid (rac)-6b showed highest potency with a pIC(50) value of 534 at GAT1 Unfortunately, the expected GAT3 potency for 2-[tris(4-methoxyphenyl)methoxy] ethyl substituted derivatives was not as high as observed for the respective nipecotic acid derivatives. (C) 2013 Elsevier Masson SAS. All rights reserved.

引用

页码：487 / 499

页数：13

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