title: Discovery of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a Potent Glycine Transporter 1 Inhibitor.
abstract: A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemotypes to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (2, SSR504734), the introduction of heteroaromatic rings enabled an increase in the GlyT1 inhibitory activity. Subsequent optimization led to the identification of 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (7w), which showed a powerful GlyT1 inhibitory activity (IC50=1.8 nM), good plasma exposure and a plasma to brain penetration in rats that was sufficient to evaluate the compound's pharmacological properties. Compound 7w showed significant effects in several rodent models for schizophrenia without causing any undesirable central nervous system side effects.
authors: Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.
authors: Shuji
authors: S
authors: Yamamoto
authors: Tsuyoshi
authors: T
authors: Shibata
authors: Kumi
authors: K
authors: Abe
authors: Koji
authors: K
authors: Oda
authors: Takeshi
authors: T
authors: Aoki
authors: Yasunori
authors: Y
authors: Kawakita
authors: Hiroshi
authors: H
authors: Kawamoto
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000613865:3-chloro-N-((S)-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)((2S)-piperidine-2-yl)methyl)-4-(trifluoromethyl)pyridine-2-carboxamide; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; C493268:SLC6A9 protein, human