Atropisomeric 4‑Phenyl‑4H‑1,2,4-triazoles as Selective Glycine Transporter 1 Inhibitors

We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbe...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-07, Vol.56 (14), p.5744-5756
Main Authors: Sugane, Takashi, Tobe, Takahiko, Hamaguchi, Wataru, Shimada, Itsuro, Maeno, Kyoichi, Miyata, Junji, Suzuki, Takeshi, Kimizuka, Tetsuya, Sakamoto, Shuichi, Tsukamoto, Shin-ichi
Format: Article
Language:English
Subjects:
Animals
Dizocilpine Maleate - pharmacology
Female
Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors
Humans
Male
Maze Learning - drug effects
Mice
Mice, Inbred ICR
Rats
Rats, Wistar
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - pharmacology
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Summary:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer ( R )-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm400383w