Delving into the Latest Updates on PF-3463275 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GlyT1

Mechanism

GlyT1 inhibitors(Glycine transporter 1 inhibitors)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Cognitive DysfunctionSchizophrenia

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H22ClFN4O

InChIKeyKYLOBHXXQOZRKK-FICVDOATSA-N

CAS Registry1173239-39-8

This is a Phase II, randomized, double-blind, placebo-controlled, cross-over POC study of stable patients with Schizophrenia or Schizoaffective disorder. The primary objective of this study is to test the efficacy of treatment with one of two does of a glycine transporter inhibitor (GlyT1I) combined with cognitive remediation to enhavce cognitive function. Subjects will be randomized to one of two doses of the glycine transporter inhibitor (GlyT1I) and placebo twice daily in addition to their antipsychotic medication for 2 treatment periods, each lasting a minimum of 5 weeks. Treatment periods will be separated by a washout period lasting approximately 3 weeks.

Start Date01 Aug 2013

Sponsor / Collaborator

Yale University

[+1]

NCT01159626 / CompletedPhase 1

A Phase 1, Randomized, Subject- and Investigator-blind, Sponsor-open, Placebo-controlled, Single- and Multiple-dose Escalation Study to Investigate the Pharmacokinetics, Safety and Tolerability of PF-03463275 in Healthy Male Japanese and Western Subjects

This Phase 1 study is the first clinical trial in Japanese subjects. The study is designed to evaluate the single- and multiple-dose pharmacokinetics, safety and tolerability of PF-03463275 oral controlled release formulation in Japanese and Western male subjects.

Start Date01 Jul 2010

Sponsor / Collaborator

Pfizer Inc.

NCT00977522 / TerminatedPhase 2

A Randomized Phase 2, Double-Blind, Placebo-Controlled, Multi-Center Study Of PF-03463275 As Add-On Therapy In Outpatients With Persistent Negative Symptoms Of Schizophrenia Treated With A Stable Dose Of A Second Generation Antipsychotic

This study is examining the efficacy of PF-03463275 compared to placebo in treating negative symptoms of schizophrenia when added to ongoing antipsychotic treatment in stable outpatients with schizophrenia.

Start Date01 Nov 2009

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-3463275

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100 Translational Medicine associated with PF-3463275

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100 Patents (Medical) associated with PF-3463275

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5

Literatures (Medical) associated with PF-3463275

01 Mar 2024·CellQ1 · BIOLOGY

Transport mechanism and pharmacology of the human GlyT1

Q1 · BIOLOGY

Article

Author: Zhao, Jun ; Meng, Yufei ; Zhao, Yan ; Li, Renjie ; Bai, Qinru ; Wei, Yiqing ; Li, Na ; Gao, Yiwei ; Hu, Tuo

The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.

01 Jun 2023·Schizophrenia research

Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia

Article

Author: D'Souza, Deepak Cyril ; Gueorguieva, Ralitza ; Ranganathan, Mohini ; Kenney, Joshua G ; Deaso, Emma ; Surti, Toral S ; Johannesen, Jason K ; Krystal, John H

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction is implicated in the impaired neuroplasticity and cognitive impairments associated with schizophrenia (CIAS). We hypothesized that enhancing NMDAR function by inhibiting the glycine transporter-1 (GLYT1) would improve neuroplasticity and thereby augment benefits of non-pharmacological cognitive training (CT) strategies. This study examined whether co-administration of a GLYT1 inhibitor and computerized CT would have synergistic effects on CIAS. Stable outpatients with schizophrenia participated in this double-blind, placebo-controlled, within-subject, crossover augmentation study. Participants received placebo or GLYT1 inhibitor (PF-03463275) for two 5-week periods separated by 2 weeks of washout. PF-03463275 doses (40 or 60 mg twice daily) were selected to produce high GLYT1 occupancy. To limit pharmacodynamic variability, only cytochrome P450 2D6 extensive metabolizers were included. Medication adherence was confirmed daily. Participants received 4 weeks of CT in each treatment period. Cognitive performance (MATRICS Consensus Cognitive Battery) and psychotic symptoms (Positive and Negative Syndrome Scale) were assessed in each period. 71 participants were randomized. PF-03463275 in combination with CT was feasible, safe, and well-tolerated at the doses prescribed but did not produce greater improvement in CIAS compared to CT alone. PF-03463275 was not associated with improved CT learning parameters. Participation in CT was associated with improvement in MCCB scores.

01 Sep 2014·Cutaneous and Ocular ToxicologyQ4 · MEDICINE

GlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats

Q4 · MEDICINE

Article

Author: Chris Somps ; Sarah Osgood ; Chang-Ning Liu ; Betty Pettersen ; Gary Seitis

CONTEXTSelective inhibitors of glycine transporter type 1 (GlyT1) increase synaptic glycine concentrations and are being developed to treat cognitive and negative symptoms of schizophrenia. However, increases in systemic glycine levels have been associated with visual disturbances and electroretinogram (ERG) alternations.OBJECTIVETo determine whether the selective GlyT1 inhibitor PF-03463275 causes changes in ERG responses in albino rats.MATERIALS AND METHODSMale Sprague-Dawley rats were administered PF-03463275 subcutaneously at 1, 3 and 10 mg/kg 1 h prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured. Plasma and vitreous samples were obtained at necropsy for determination of PF-03463275 concentrations.RESULTSA dose-dependent reduction (up to ∼70%) in the amplitude of the scotopic ERG oscillatory potentials (OPs) was observed following PF-03463275 administration. The amplitude of the OPs was also negatively correlated to the concentration of PF-03463275 in the vitreous humor (r = -0.64, p < 0.0001). With the exception of a small increase in scotopic ERG a-wave amplitude and latency no effects were observed on other ERG parameters tested.CONCLUSIONSWe conclude that inhibition of the GlyT1 transporter in the retina causes ERG changes which may underlie recent reports of visual disturbance with GlyT1 inhibitors in clinical trials.

100 Deals associated with PF-3463275

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