贝非拉醇(Befiradol Fumarate) - 药物靶点：5-HT1A receptor_在研适应症：药物性运动障碍，帕金森病，糖尿病性神经病变_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Befiradol、F-13640、NLX 112

+ [1]

靶点

5-HT1A receptor

作用机制

5-HT1A receptor激动剂(5-羟色胺1A受体激动剂)

治疗领域

神经系统疾病内分泌与代谢疾病遗传病与畸形+ [1]

在研适应症

药物性运动障碍帕金森病糖尿病性神经病变+ [1]

非在研适应症

原研机构

在研机构

非在研机构

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

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结构

分子式C24H26ClF2N3O5

InChIKeyHCRQBLXXJOROBP-WLHGVMLRSA-N

CAS号208110-65-0

关联

11

项与贝非拉醇相关的临床试验

NCT05148884 / Completed临床2期

A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in Levodopa-induced Dyskinesia in Parkinson's Disease

This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks.

开始日期2021-11-09

申办/合作机构

Neurolixis, Inc.

[+2]

EUCTR2020-006053-22-SE / Unknown status临床2期

A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 versus Placebo in Levodopa-induced Dyskinesia in Parkinson’s Disease

开始日期2021-09-22

申办/合作机构

Neurolixis, Inc.

NCT03347331 / Completed早期临床1期IIT

First-in-man Study of [18F]-F13640, a PET Radiopharmaceutical for Functional 5-HT1A Receptor Imaging

This clinical assay is designed to validate that [18F]F13640 as a radiotracer of 5-HT1A functional receptors. A first group of healthy subjects underwent a PET scan with arterial blood sampling to determine the kinetic model of the tracer. A second group of healthy subjects underwent a classical test-retest study (i.e two distant PET scans) to determine the reproducibility of measures.

开始日期2018-04-23

申办/合作机构

Hospices Civils de Lyon

100 项与贝非拉醇相关的临床结果

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100 项与贝非拉醇相关的转化医学

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100 项与贝非拉醇相关的专利（医药）

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50

项与贝非拉醇相关的文献（医药）

2024-03-01·Neuropharmacology

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

Article

作者: Canal, Clinton E ; Tyagi, Richa ; Chen, Yiming ; Saraf, Tanishka S

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT_1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT_1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT_1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT_1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT_1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT_1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT_1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT_1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT_1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT_1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT_1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT_1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

2023-05-01·European journal of nuclear medicine and molecular imaging

[18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans

Article

作者: Isal, Sibel ; Merida, Inés ; Zimmer, Luc ; Redoute, Jérôme ; Costes, Nicolas ; Dailler, Frédéric ; Iecker, Thibaut ; Colom, Matthieu ; Le Bars, Didier ; Courault, Pierre ; Gobert, Florent ; Newman-Tancredi, Adrian ; Lancelot, Sophie

Purpose:

F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification.

Methods:

PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF).

Results:

[18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions.

Conclusion:

The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry.

Trial Registration.:

Trial Registration EudraCT 2017–002,722-21.

2023-01-01·NeuroImage. Clinical

Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

Article

作者: Depoortere, Ronan ; Levigoureux, Elise ; Newman-Tancredi, Adrian ; Chaib, Sarah ; Vidal, Benjamin ; Bouillot, Caroline ; Zimmer, Luc

INTRODUCTION:

The leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT_1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion.

METHODS:

We compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [¹⁸F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112.

RESULTS:

In HPK-non-LID rats, [¹⁸F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT_1A receptors.

CONCLUSION:

This neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT_1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson's disease.

1

项与贝非拉醇相关的新闻（医药）

2023-08-16

·Pharmaceutical Technology

Avidity gains FDA orphan drug designation for DMD therapy

DMD is a rare genetic condition that causes gradual muscle damage and weakness. Credit: StudioMolekuul/Shutterstock.com. Avidity Biosciences has obtained orphan drug designation from the US Food and Drug Administration (FDA) for its AOC 1044 to treat Duchenne muscular dystrophy (DMD) in people with mutations amenable to exon 44 skipping (DMD44). DMD is a rare, early-onset genetic condition that causes gradual muscle damage and weakness due to the loss of the dystrophin protein. Recommended Reports Reports LOA and PTSR Model - Mesdopetam in Drug-Induced Dyskinesia GlobalData Reports LOA and PTSR Model - Befiradol in Drug-Induced Dyskinesia GlobalData View all Companies Intelligence Avidity Biosciences Inc Avidity LLC AOC AG View all AOC 1044 provides phosphorodiamidate morpholino oligomers to skeletal muscles and cardiac tissue. Its purpose is to selectively exclude exon 44 of the dystrophin gene, thereby facilitating the production of dystrophin. The Phase 1/2 EXPLORE44 clinical trial is currently evaluating AOC 1044 as a treatment for individuals with DMD44. It marks the initial step in assessing a series of AOCs being developed by the company to address DMD. Avidity intends to disclose findings from the EXPLORE44 trial’s segment involving healthy volunteers in the fourth quarter of 2023. It is currently enrolling participants living with DMD44 in the trial. In April 2023, the company secured fast-track designation from the FDA for AOC 1044 to treat DMD44. Avidity chief medical officer Steve Hughes stated: “There are currently no treatment options that target the underlying cause of DMD44. AOC 1044 is designed to specifically skip exon 44 of the dystrophin gene to enable the production of functional dystrophin protein. “We look forward to advancing AOC 1044 in clinical development and bringing this very important treatment to patients as quickly and safely as possible.”

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100 项与贝非拉醇相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	贝非拉醇	-	-

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
药物性运动障碍	临床2期	瑞典	Neurolixis, Inc.	2021-11-09
帕金森病	临床2期	瑞典	Neurolixis, Inc.	2021-11-09
糖尿病周围神经病变	临床2期	法国	Pierre Fabre SA	2010-06-18
癌症疼痛	临床2期	捷克	Neurolixis, Inc.	-
癌症疼痛	临床2期	法国	Neurolixis, Inc.	-
癌症疼痛	临床2期	匈牙利	Neurolixis, Inc.	-
糖尿病性神经病变	临床2期	-	Neurolixis, Inc.	-
神经痛	临床2期	比利时	Neurolixis, Inc.	-
神经痛	临床2期	芬兰	Neurolixis, Inc.	-
神经痛	临床2期	法国	Neurolixis, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05148884 (CTgov)	临床2期	药物性运动障碍 \| 帕金森病	27	NLX-112 (NLX-112)	窪鹹積蓋蓋獵簾糧壓築(構襯餘觸顧艱鹽餘積膚) = 衊積鏇艱衊鏇築鏇鹽膚簾製襯積簾觸憲淵製繭 (膚蓋鬱積壓餘淵築憲壓, 餘憲齋廠選製觸製選艱 ~ 範醖繭壓淵鬱醖構築製) 更多	-	2024-04-23
				Placebo (Placebo)	窪鹹積蓋蓋獵簾糧壓築(構襯餘觸顧艱鹽餘積膚) = 壓鹹壓壓窪壓願齋鏇製簾製襯積簾觸憲淵製繭 (膚蓋鬱積壓餘淵築憲壓, 膚簾鬱鏇遞鏇夢衊壓繭 ~ 網願製餘鏇製網製觸築) 更多