title: Atropisomeric 4-phenyl-4H-1,2,4-triazoles as selective glycine transporter 1 inhibitors.
abstract: 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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc. , 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugane
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tobe
authors.forename: Wataru
authors.initials: W
authors.lastname: Hamaguchi
authors.forename: Itsuro
authors.initials: I
authors.lastname: Shimada
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Maeno
authors.forename: Junji
authors.initials: J
authors.lastname: Miyata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimizuka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; C493268:SLC6A9 protein, human; D014230:Triazoles; D016291:Dizocilpine Maleate