Identification of 1-Methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor.
We previously identified 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (5, TP0439150) as a potent and orally available glycine transporter 1 (GlyT1) inhibitor. In this article, we describe our identification of 1-methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide (7n) as a structurally diverse back-up compound of 5, using central nervous system multiparameter optimization (CNS MPO) as a drug-likeness guideline. Compound 7n showed a higher CNS MPO score and different physicochemical properties as compared to 5. Compound 7n exhibited potent GlyT1 inhibitory activity, a favorable pharmacokinetics profile, and elicited an increase in the cerebrospinal fluid (CSF) concentration of glycine in rats.
Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
Shuji
S
Yamamoto
Hiroshi
H
Ohta
Kumi
K
Abe
Daiji
D
Kambe
Naohiro
N
Tsukiyama
Yasunori
Y
Kawakita
Minoru
M
Moriya
Akito
A
Yasuhara
D000284:Administration, Oral; D000818:Animals; D002555:Cerebrospinal Fluid / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
C000613626:1-methyl-N-(propan-2-yl)-N-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methyl)-1H-imidazole-4-carboxamide; D050487:Glycine Plasma Membrane Transport Proteins; D007093:Imidazoles; D011725:Pyridines; C493268:SLC6A9 protein, human