AUT-00206(AUT-00206) - 药物靶点：Kv3.1_专利_临床

概要

基本信息

药物类型

小分子化药

别名

5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4- yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione

靶点

Kv3.1

作用机制

Kv3.1调节剂(电压门控性钾通道蛋白亚型Kv3.1调节剂)

治疗领域

神经系统疾病遗传病与畸形其他疾病

在研适应症-

非在研适应症

脆性X综合征精神分裂症

原研机构

Autifony Therapeutics Ltd.

在研机构-

非在研机构

Autifony Therapeutics Ltd.

最高研发阶段无进展临床1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C20H20N4O4

InChIKeyJYHHQTRVJFMEGR-UHFFFAOYSA-N

CAS号1380696-64-9

关联

4

项与 AUT-00206 相关的临床试验

ISRCTN80267019 / Completed临床1期

A randomised, double-blind, placebo-controlled, single and repeated dose escalation study to assess the safety, tolerability, pharmacokinetics and food effect of a new formulation of AUT00206 in healthy men and women

开始日期2021-09-01

申办/合作机构

Autifony Therapeutics Ltd.

NCT03164876 / Completed临床1期

A Randomised, Double-blind, Placebo-controlled Study of the Safety, Pharmacokinetics and Exploratory Pharmacodynamics of AUT00206 for 28 Days as Adjunctive Therapy in Patients With Recently Diagnosed Schizophrenia

This study will investigate the safety, tolerability, PK and PD profile of AUT00206 after repeated doses in patients with stable but symptomatic schizophrenia, taking one or two established anti-psychotic drugs. The subjects will undergo brain imaging, tests of cognition and tests of auditory function and electrophysiological measures in addition to routine safety monitoring. Because of the pioneering and novel mechanism of action of this drug, a key objective is to characterize this range of biomarkers which will inform the future development of the drug.

开始日期2017-04-20

申办/合作机构

Autifony Therapeutics Ltd.

[+1]

NCT02935725 / Completed临床1期

A Phase 1, Single-centre, Double-blind, Placebocontrolled Crossover Study to Assess the pharmacoMRI Effects of AUT00206 in Healthy Male Participants

A Phase 1, Single-centre, Double-blind, Placebo controlled Crossover Study to Assess the pharmacoMRI Effects of AUT00206 in Healthy Male Participants

开始日期2016-10-01

申办/合作机构

Autifony Therapeutics Ltd.

[+1]

100 项与 AUT-00206 相关的临床结果

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100 项与 AUT-00206 相关的转化医学

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100 项与 AUT-00206 相关的专利（医药）

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8

项与 AUT-00206 相关的文献（医药）

2024-03-01·Clinical EEG and Neuroscience

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction

Article

作者: Kaar, Stephen J. ; Howes, Oliver D. ; Nottage, Judith F. ; Angelescu, Ilinca ; Marques, Tiago Reis

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35–45 Hz) power ( n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power ( t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

2024-02-01·Cell Reports Medicine

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy

Article

作者: Somarowthu, Ala ; Akizu, Naiara ; Hoddeson, Emily ; Gunthorpe, Martin J ; Goldberg, Ethan M ; Lopez, Emily ; Koutcher, Carly ; Kaneko, Keisuke ; Large, Charles H ; Flores-Mendez, Marco ; Wengert, Eric R ; Lee, Demetrius ; Feng, Huijie ; Arias, Leroy ; Liang, Qiansheng ; Clatot, Jerome ; Zhang, Xiaohong ; Covarrubias, Manuel

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.

2023-12-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Pharmacological modulation of Kv3 voltage-gated potassium channels regulates fear discrimination and expression in a response-dependent manner

Article

作者: Stevenson, Carl W ; Day, Harriet L L ; Smith, Jessica ; Stubbendorff, Christine ; Hale, Ed ; Alvaro, Giuseppe S ; Large, Charles H

Various psychiatric diseases are characterized by aberrant cognition and emotional regulation. This includes inappropriately attributing affective salience to innocuous cues, which can be investigated using translationally relevant preclinical models of fear discrimination. Activity in the underpinning corticolimbic circuitry is governed by parvalbumin-expressing GABAergic interneurons, which also regulate fear discrimination. Kv3 voltage-gated potassium channels are highly expressed in these neurons and are important for controlling their activity, suggesting that pharmacological Kv3 modulation may regulate fear discrimination. We determined the effect of the positive Kv3 modulator AUT00206 given systemically to female rats undergoing limited or extended auditory fear discrimination training, which we have previously shown results in more discrimination or generalization, respectively, based on freezing at retrieval. We also characterized darting and other active fear-related responses. We found that limited training resulted in more discrimination based on freezing, which was unaffected by AUT00206. In contrast, extended training resulted in more generalization based on freezing and the emergence of discrimination based on darting during training and, to a lesser extent, at retrieval. Importantly, AUT00206 given before extended training had dissociable effects on fear discrimination and expression at retrieval depending on the response examined. While AUT00206 mitigated generalization without affecting expression based on freezing, it reduced expression without affecting discrimination based on darting, although darting levels were low overall. These results indicate that pharmacological Kv3 modulation regulates fear discrimination and expression in a response-dependent manner. They also raise the possibility that targeting Kv3 channels may ameliorate perturbed cognition and emotional regulation in psychiatric disease.

100 项与 AUT-00206 相关的药物交易

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