Background:
- A small brain protein called the metabotropic glutamate receptor subtype 5 (mGluR5) may affect several brain diseases such as autism and depression. Researchers will use 2 radioactive chemicals ([11C]SP203 and [11C]FPEB) and a research drug (STX107) that can attach to the receptor, to figure out the best way to use positron emission tomography (PET) to see the mGluR5 receptor. They will use scans to monitor where the radioactivity goes.
Objectives:
- To find the best way to image the mGluR5 receptor in the brain.
Eligibility:
- Healthy volunteers ages 18 to 55.
Design:
All participants will be screened with a medical exam at visit 1. In later visits, they may have a PET scan, when two small tubes are placed under the skin and they lie down in a scanner. They may have an MRI scan, when they lie down in a scanner.
Part 1 participants will have 2 more visits. They will have a PET brain scan using [11C]FPEB and will have blood drawn. Then they will have an MRI brain scan.
Part 2 participants will have 1 more visit, with a whole body PET scan using [11C]FPEB and blood drawn.
Part 3 participants will have 4 more visits, including 1 overnight stay at a hospital. Over all the visits, they will have 4 PET scans and 1 MRI brain scan. They will receive the research drug and injections of both chemicals. Blood will be drawn during the scans.

开始日期2013-06-27

申办/合作机构

National Institute of Mental Health

NCT01325740 / Suspended临床2期

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of STX107 in Adults With Fragile X Syndrome

The study will consist of a Screening period (up to 14 days), a Treatment period, and a Follow-Up period. Sixteen subjects will be enrolled into two sequential dose cohorts - 10 or 30 mg (or matching placebo) across four study centers.

开始日期2011-05-01

申办/合作机构

Seaside Therapeutics LLC

NCT00965432 / Completed临床1期

A Single-Dose, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study in Healthy, Normal Volunteers to Assess the Safety, Tolerability and Pharmacokinetics of STX107

The objectives of this study are to determine the safety and tolerability of single oral doses of STX107 and to determine basic pharmacokinetic (PK) parameters following single oral doses of STX107 when administered via an oral suspension

开始日期2009-09-01

申办/合作机构

Seaside Therapeutics LLC

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100 项与 STX-107 相关的临床结果

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100 项与 STX-107 相关的转化医学

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100 项与 STX-107 相关的专利（医药）

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项与 STX-107 相关的文献（医药）

2020-07-01·Molecular Pharmacology3区 · 医学

Detailed In Vitro Pharmacological Characterization of Clinically Tested Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5

3区 · 医学

Article

作者: Arsova, Angela ; Hansen, Jakob Lerche ; Vedel, Line ; Møller, Thor C ; Foster, Simon R ; Bräuner-Osborne, Hans ; Gregory, Karen J

Negative allosteric modulation of the metabotropic glutamate 5 (mGlu₅) receptor has emerged as a potential strategy for the treatment of neurologic disorders. Despite the success in preclinical studies, many mGlu₅ negative allosteric modulators (NAMs) that have reached clinical trials failed due to lack of efficacy. In this study, we provide a detailed in vitro pharmacological characterization of nine clinically and preclinically tested NAMs. We evaluated inhibition of l-glutamate-induced signaling with Ca²⁺ mobilization, inositol monophosphate (IP₁) accumulation, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and real-time receptor internalization assays on rat mGlu₅ expressed in HEK293A cells. Moreover, we determined association rates (k_on) and dissociation rates (k_off), as well as NAM affinities with [³H]methoxy-PEPy binding experiments. k_on and k_off values varied greatly between the nine NAMs (34- and 139-fold, respectively) resulting in long receptor residence times (>400 min) for basimglurant and mavoglurant, medium residence times (10-30 min) for AZD2066, remeglurant, and (RS)-remeglurant, and low residence times (<10 mins) for dipraglurant, F169521, F1699611, and STX107. We found that all NAMs inhibited l-glutamate-induced mGlu₅ receptor internalization, generally with a similar potency to IP₁ accumulation and ERK1/2 phosphorylation, whereas Ca²⁺ mobilization was less potently inhibited. Operational model of allosterism analyses revealed that dipraglurant and (RS)-remeglurant were biased toward (affinity) receptor internalization and away (cooperativity) from the ERK1/2 phosphorylation pathway, respectively. Our study is the first to measure mGlu₅ NAM binding kinetics and negative allosteric modulation of mGlu₅ receptor internalization and adds significant new knowledge about the molecular pharmacology of a diverse range of clinically relevant NAMs. SIGNIFICANCE STATEMENT: The metabotropic glutamate 5 (mGlu₅) receptor is important in many brain functions and implicated in several neurological pathologies. Negative allosteric modulators (NAMs) have shown promising results in preclinical models but have so far failed in human clinical trials. Here we provide the most comprehensive and comparative molecular pharmacological study to date of nine preclinically/clinically tested NAMs at the mGlu₅ receptor, which is also the first study to measure ligand binding kinetics and negative allosteric modulation of mGlu₅ receptor internalization.

2018-06-20·ACS Chemical Neuroscience3区 · 医学

Exploring the Binding Mechanism of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators in Clinical Trials by Molecular Dynamics Simulations

3区 · 医学

Article

作者: Yang, Fengyuan ; Tu, Gao ; Zheng, Guoxun ; Xue, Weiwei ; Zhu, Feng ; Li, Xiaofeng ; Fu, Tingting ; Chen, Yuzong ; Yao, Xiaojun

Metabotropic glutamate receptor 5 (mGlu₅) plays a key role in synaptic information storage and memory, which is a well-known target for a variety of psychiatric and neurodegenerative disorders. In recent years, the increasing efforts have been focused on the design of allosteric modulators, and the negative allosteric modulators (NAMs) are the front-runners. Recently, the architecture of the transmembrane (TM) domain of mGlu₅ receptor has been determined by crystallographic experiment. However, it has been not well understood how the pharmacophores of NAMs accommodated into the allosteric binding site. In this study, molecular dynamics (MD) simulations were performed on mGlu₅ receptor bound with NAMs in preclinical or clinical development to shed light on this issue. In order to identify the key residues, the binding free energies as well as per-residue contributions for NAMs binding to mGlu₅ receptor were calculated. Subsequently, the in silico site-directed mutagenesis of the key residues was performed to verify the accuracy of simulation models. As a result, the shared common features of the studied 5 clinically important NAMs (mavoglurant, dipraglurant, basimglurant, STX107, and fenobam) interacting with 11 residues in allosteric site were obtained. This comprehensive study presented a better understanding of mGlu₅ receptor NAMs binding mechanism, which would be further used as a useful framework to assess and discover novel lead scaffolds for NAMs.

2012-12-01·Biological Psychiatry1区 · 医学

Lifting the Mood on Treating Fragile X

1区 · 医学

Article

作者: Peter C. Kind ; Emily K. Osterweil ; Mark F. Bear

i o t r h m o O nly a decade ago, it was believed that a genetic diagnosis of intellectual disability and autism offered little in the way of hope for a medical treatment to lessen the burden on the ffected individuals and their families. However, recent research imed at understanding the cellular and molecular mechanisms hat underlie the pathogenesis of ASD has ushered in a new era of argeted treatment strategies. Studies in fragile X syndrome (FXS) ave been at the forefront of this revolution, and they are forging a ath that could define future approaches to the treatment of ASD. FXS is the leading identified genetic cause of autism. Because it s a defined genetic disorder that can be effectively modeled in nimals, the study of FXS has great potential to yield information bout the pathophysiology of ASD. FXS is caused by a silencing of he FMR1 gene and the loss of fragile X mental retardation protein FMRP), a repressor of mRNA translation. Early studies suggested hat synaptic protein synthesis is stimulated by activation of group (Gp1) metabotropic glutamate receptors (comprising mGluR1 nd mGluR5) and that one functional consequence of this protein ynthesis is the long-term depression (LTD) of synaptic strength reviewed in in Bhakar et al. [1]). The subsequent discovery that LTD s elevated in the mouse model of FXS (Fmr1 ) led to the proposal hat multiple symptoms of the disease might be accounted for by eightened responsiveness to Gp1 mGluR activation. This mGluR heory of fragile X predicted that the antagonism of Gp1 mGluRs hould correct pathologic changes in FXS (2). In the decade that lapsed since it was first proposed, numerous studies in a range of nimal models have validated this theory. The animal data show hat many aspects of FXS can be accounted for by altered Gp1 GluR signaling at synapses. This insight is the basis for multiple linical trials that are now underway in FXS (for extensive reviews ee Bhakar et al. [1] and Krueger and Bear [3]). The first clinical test of the mGluR theory was a small, open-label rial using fenobam, a Gp1 mGluR antagonist that is highly selective or mGluR5. The results of this small trial showed beneficial effects n a subset of the adult FXS patients tested; however, it is important o note that no placebo control group was included in this trial, nor as it performed in an experimenter blind fashion (4). Since this nitial study, multiple large-scale placebo-controlled trials have been nitiated with selective mGluR5 negative allosteric modulators— amely, STX107 (Seaside Therapeutics, Cambridge, Massachusetts), G7090 (Hoffman-LaRoche, Basel, Switzerland), and AFQ056 (Novartis, asel, Switzerland). Although the results of most of these trials have yet o be revealed, in post hoc analysis of Phase II data AFQ056 was reorted to show an improvement on multiple behavioral tests in adult atients with a fully methylated (silenced) FMR1 gene. In tandem with drugs that directly interfere with mGluR5, other rugs that may indirectly target Gp1 mGluR signaling are also being ested in clinical trials. One strategy for reducing mGluR activation is

100 项与 STX-107 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脆性X综合征	临床2期	美国	Seaside Therapeutics LLC	2011-05-01
脆性X综合征	临床2期	美国	Seaside Therapeutics LLC	2011-05-01
自闭症	临床2期	美国	Seaside Therapeutics LLC	2009-09-30