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

Abstract

These results suggest that GlyT1 inhibitors including TASP0315003 may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects.

Discovery of 3-Chloro-<i>N</i>-{(<i>S</i>)-[3-(1-ethyl-1<i>H</i>-pyrazol-4-yl)phenyl][(2<i>S</i>)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a Potent Glycine Transporter 1 Inhibitor

“…The detailed pharmacological properties of 7w have already been reported. 20) Compound 7w significantly improved MK-801-impaired cognition in social recognition tests performed in rats at a dose of 0.1 mg/kg orally and also significantly reversed the phencyclidine-induced reduction in the social interaction of paired mice at a dose of 0.3 mg/kg orally. These studies may reflect the cognitive dysfunction and negative symptom of schizophrenia, respectively.…”

“…19) Recently, we reported the pharmacological profiles of 7w (TP0439150), which showed a potent in vitro glycine uptake inhibitory activity in rats (IC 50 =1.5 nM) and exhibited significant effects in a rodent model of negative symptoms and cognitive impairment associated with schizophrenia. 20) In the present article, we describe the medicinal chemistry efforts that resulted in the potent inhibitor 7w.…”

“…4 mol/L HCl in EtOAc solution (0.2 mL) was added to a solution of the free form of 7a in EtOAc (1 mL), and the precipitate was filtered to yield 7a (202 mg, 62%) as a colorless powder. (20 …”

Identification of 1-Methyl-<i>N</i>-(propan-2-yl)-<i>N</i>-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1<i>H</i>-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor

“…14,15) Recently, our group discovered 5 (TP0439150), and reported its pharmacological profile. 16) Compound 5 shows potent in vitro GlyT1 inhibitory activity with an IC 50 value of 1.8 nM; oral dosing at 1 mg/kg elicited an increase in the concentration of glycine in the cerebrospinal fluid (CSF) in rats. Furthermore, at doses of 0.1 and 0.3 mg/ kg, respectively, 5 significantly improved cognitive deficit induced by MK-801 in the social recognition test in rats and reversed the reduction in social interaction induced by repeated phencyclidine treatment in mice.…”

A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

“…[12][13][14] Additionally, GlyT1 has been reported to be a target for the treatment of schizophrenia. 10,[15][16][17] Despite the fact that some GlyT1 inhibitors activate the NMDA receptor, potentially increasing the risk of seizure, a large number of studies indicate that GlyT1 inhibitors can be used as anticonvulsants for a variety of seizures. 18,19) 21) suggesting GlyT1 as a potential target for antiepileptic drugs.…”