PF-03463275
目录号 : GC60284PF-03463275是一种中枢神经系统渗透性、具有口服活性、选择性、竞争性甘氨酸转运蛋白-1(GlyT1)可逆抑制剂,Ki为11.6nM。PF-03463275有可能用于精神分裂症的研究。
Cas No.:1173239-39-8
Sample solution is provided at 25 µL, 10mM.
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PF-03463275 is a centrally penetrant, orally available, selective, and competitive GlyT1 (glycine transporter-1) reversible inhibitor, with a Ki of 11.6 nM. PF-03463275 has the potential for Schizophrenia research[1][2].
PF-03463275 (1-10 mg/kg; s.c.) attenuates oscillatory potentials (OPs)[2]. Animal Model: Male Sprague-Dawley rats[2]
[1]. Lowe JA 3rd, et al. The discovery of a structurally novel class of inhibitors of the type 1 glycine transporter [published correction appears in Bioorg Med Chem Lett. 2009 Aug 15;19(16):4885. Bronk, Brian S [added]; Schaeffer, Eric [added]]. Bioorg Med Chem Lett. 2009;19(11):2974-2976. [2]. Liu CN, Pettersen B, Seitis G, Osgood S, Somps C. GlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats. Cutan Ocul Toxicol. 2014;33(3):206-211.
Cas No. | 1173239-39-8 | SDF | |
Canonical SMILES | O=C(C(N=C1)=CN1C)N(CC(C=C2)=CC(Cl)=C2F)C[C@@H]3[C@](C4)([H])[C@@]3([H])CN4C | ||
分子式 | C19H22ClFN4O | 分子量 | 376.86 |
溶解度 | DMSO: 33.33 mg/mL (88.44 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.6535 mL | 13.2675 mL | 26.5351 mL |
5 mM | 0.5307 mL | 2.6535 mL | 5.307 mL |
10 mM | 0.2654 mL | 1.3268 mL | 2.6535 mL |
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Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
Biol Psychiatry 2018 Sep 15;84(6):413-421.PMID:29499855DOI:10.1016/j.biopsych.2017.12.019.
Background: Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. Methods: In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography and 18F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a "working memory" circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). Results: PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ∼44%, 61%, 76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine-induced effects but did improve working memory accuracy in healthy control subjects. PF-03463275 increased long-term potentiation only in SZs with peak effects at 40 mg twice a day (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated. Conclusions: The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating N-methyl-D-aspartate receptor function in the ketamine assay, it enhanced neuroplasticity in SZs. These findings provide support for a clinical trial to test the ability of PF-03463275 to enhance cognitive remediation toward addressing cognitive impairments associated with schizophrenia.
GlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats
Cutan Ocul Toxicol 2014 Sep;33(3):206-11.PMID:24147951DOI:10.3109/15569527.2013.833937.
Context: Selective 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. Objective: To determine whether the selective GlyT1 inhibitor PF-03463275 causes changes in ERG responses in albino rats. Materials and methods: Male 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. Results: A 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. Conclusions: We 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.
American Chemical Society--238th National Meeting & Exposition. Developments in medicinal chemistry: part 1. 16-20 August 2009, Washington DC, USA
IDrugs 2009 Oct;12(10):605-7.PMID:19790004doi
The 238th National Meeting and Exposition of the American Chemical Society, held in Washington DC, included topics covering new compounds and developments in the field of medicinal chemistry. This conference report highlights selected presentations on a novel KV1.5 blocker, a state-dependent CaV2.2 antagonist, therapeutic uses of macrocycles, a novel P2X7 antagonist, developments using the StaR technology platform, the optimization of a neuropeptide S receptor antagonist, and type 1 glycine transport modulators. Investigational drugs discussed include WYE-160020 (Wyeth), Trox-1 (Neuromed Pharmaceuticals Inc), ulimorelin (Tranzyme Pharma Inc), E-32224 (Ensemble Discovery Corp) and PF-03463275 (Pfizer Inc); the discontinued compound AZD-9056 is also highlighted.