The synthesis and SAR of 2-arylsulfanyl-phenyl piperazinyl acetic acids as glyT-1 inhibitors

Smith, Garrick; Ruhland, Thomas; Mikkelsen, Gitte Kobberøe; Andersen, Kim; Christoffersen, Claus T.; Alifrangis, Lene; Mørk, Arne; Wren, Stephen P.; Harris, Neil V.; Wyman, B. M.; Brandt, Guillaume

doi:10.1016/j.bmcl.2004.05.043

Cited by 32 publications

(14 citation statements)

References 10 publications

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“…9), which was shown to elevate extracellular glycine levels in the rat ventral hippocampus, as measured by in vivo microdialysis at doses of 1.2-4.6 mg/kg (s.c.) [80]. Furthermore, the same group reported (Fig.…”

Section: Non-sarcosine-derived Glyt-1 Inhibitorssupporting

confidence: 69%

Glycine Transporter-1: A New Potential Therapeutic Target for Schizophrenia

Hashimoto¹

2011

Current Pharmaceutical Design

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The hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory site on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. A recent double blind phase II study demonstrated that the novel GlyT-1 inhibitor RG1678 has a robust and clinically meaningful effect in patients with schizophrenia. In this article, the author reviews the recent findings on the GlyT-1 as a potential therapeutic target of schizophrenia.

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Section: Non-sarcosine-derived Glyt-1 Inhibitorssupporting

confidence: 69%

Glycine Transporter-1: A New Potential Therapeutic Target for Schizophrenia

Hashimoto¹

2011

Current Pharmaceutical Design

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“…This effect of SSR504734 was stereoselective since the (R,R) enantiomer SSR506204 was far less potent. SSR504734 inhibited glycine transport at human and rat GlyT1s (IC 50 s ca 20 nM) with a potency in between that reported SSR504734, a reversible GlyT1 inhibitorfor ALX5407 (3 nM, Atkinson et al, 2001;220 nM, Herdon et al, 2001, both for hGlyT1c; 26 nM for hGlyT1b, Smith et al, 2004; 10 nM for rGlyT1a, Kinney et al, 2003) and for ORG 24598 (120 nM for hGlyT1b, Brown et al, 2001), and far above that of sarcosine or glycyldodecylamide, two earlier GlyT1 inhibitors (IC 50 s greater than 10 mM; present results; Javitt and Frusciante, 1997). SSR504734 was similarly potent in mice (IC 50 : 3875 nM, in cortical homogenate, not reported in Materials and methods and Results), a point we verified because of the use of this species in several tests.…”

Section: Ssr504734 Is a Selective Blocker Of Glyt1 In Vitro And Ex Vivomentioning

confidence: 51%

Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic

Depoortère

Dargazanli

Estenne-Bouhtou

et al. 2005

Neuropsychopharmacol

216

161

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Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

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“…The prototypic GLYT1-selective substrate Nmethyl glycine (sarcosine) has formed the basis for generations of highly potent and selective derivatives, including N- [3-(4Ј- (Bergeron et al, 1998;Atkinson et al, 2001;Aubrey and Vandenberg, 2001;Brown et al, 2001;Lowe et al, 2003;Mezler et al, 2008;Perry et al, 2008) (Table 5). For nonsarcosine GLYT1 inhibitors, several structurally diverse compounds have emerged from drug discovery programs, such as ((2-(4-benzo(1,3)dioxol-5-yl-2-tert-butylphenoxy) ethyl)methylamino)acetic acid (LY2365109) (Perry et al, 2008), 2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide (SSR504734) (Depoortère et al, 2005), SSR130800 (Boulay et al, 2008), N- [3-(4-chlorophenyl)-3-[4-(2-thiazolylcarbonyl)phenoxy]propyl]-N-methyl-glycine (CP-802,079) , and (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (Lu AA20465) (Smith et al, 2004), in addition to a series of cyclic tetrapeptides that was recently isolated from a soil bacteria (Terui et al, 2008). These compounds are excellent tools for studying the modulatory role of GLYT1 in neurotransmission [for example, in N-methyl-D-aspartate (NMDA) receptormediated signaling and plasticity at excitatory synapses (Bergeron et al, 1998;Kinney et al, 2003) as well as glycinergic signaling at inhibitory synapses (Bradaïa et al, 2004)].…”

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confidence: 99%