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.

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.

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.

Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia.

Rationale: Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia.

Objectives: We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics.

Results: A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats.

Complete sequencing and characterization of 21,243 full-length human cDNAs.

As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding.