Flindokalner(Flindokalner) - 药物靶点：BK channel_在研适应症：癫痫性脑病，缺血性卒中_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Flindokalner (USAN/INN)

+ [1]

靶点

BK channel

作用方式

激动剂

作用机制

BK channel激动剂(钙激活钾通道α/β1复合体激动剂)

治疗领域

神经系统疾病心血管疾病

在研适应症

癫痫性脑病缺血性卒中

非在研适应症-

原研机构

Bristol Myers Squibb Co.

在研机构

University of Montréal

Bristol Myers Squibb Co.

The University of Edinburgh

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C16H10ClF4NO2

InChIKeyULYONBAOIMCNEH-HNNXBMFYSA-N

CAS号187523-35-9

关联

2

项与 Flindokalner 相关的临床试验

NCT05378074

/ Unknown statusN/AIIT

Hypersensitivity to Opening of BKCa Channels in Post-Traumatic Headache: A Randomized Clinical Trial

The aim is to investigate whether opening of large conductance calcium-activated potassium (BKCa) channels induces headache with migraine-like features in people with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI).

开始日期2022-09-01

申办/合作机构

Danish Headache Center

NCT03887325

/ CompletedN/AIIT

To Investigate the Headache Induction and the Cerebral Hemodynamic Changes After Infusion of Maxipost in Healthy Volunteers and Migraine Patients

It is not previously investigated whether, there is a correlation between potassium channels and migraine, so it is unclear whether, this signaling pathway through potassium channels has an impact on migraine pathophysiology.
Maxipost (BMS 204352) is a vasoactive molecule that causes vasodilation via the big calcium dependent potassium (BKCa) channel signaling pathway. Maxipost decreases the blood pressure and maxipost infusion causes headache in healthy volunteers. A possible coherence between maxipost and headache/migraine in healthy volunteers and migraine patients is yet to be investigated.
The present study aims to clarify a possible coherence between maxipost and headache/migraine and it will help to shed light on the importance of potassium channels in migraine. In general, the study will contribute to a greater understanding of migraine pathogenesis and possibly lead to development of specific migraine treatment.

开始日期2019-04-01

申办/合作机构

Danish Headache Center

100 项与 Flindokalner 相关的临床结果

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100 项与 Flindokalner 相关的转化医学

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100 项与 Flindokalner 相关的专利（医药）

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89

项与 Flindokalner 相关的文献（医药）

2024-02-01·Molecular Psychiatry

Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice

Article

作者: Roberts, Amanda J ; Fleck, Kiera ; Bajo, Michal ; Lopez, Catherine ; Gandhi, Pauravi J ; Contet, Candice ; Homanics, Gregg E ; Kreifeldt, Max ; Martinez, Briana ; Bhattacharyya, Pushpita ; Okhuarobo, Agbonlahor ; Dopico, Alex M ; Roberto, Marisa

AbstractLarge conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol’s direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.

2023-05-01·eneuro

A Targeted, Low-Throughput Compound Screen in aDrosophilaModel of Neurofibromatosis Type 1 Identifies Simvastatin and BMS-204352 as Potential Therapies for Autism Spectrum Disorder (ASD)

Article

作者: Garg, Shruti ; Baines, Richard A ; Dyson, Alex ; Ryan, Megan ; Evans, D Gareth

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments.Drosophilalarvae lackingNf1expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behavior is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss ofNf1expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutiveNf1knock-down is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behavior. With such a feeding regime, we identify two compounds from a targeted, low-throughput screen that significantly and consistently reduce, but do not fully rescue, tactile hypersensitivity inNf1P1larvae. These are the HMG CoA-reductase inhibitor simvastatin, and the BKCachannel activator BMS-204352. At the NMJ, both compounds induce a significant reduction in the enhanced spontaneous transmission frequency ofNf1P1larvae, though again not to the level of vehicle-treated controls. However, both compounds fully rescue the increased quantal size ofNf1P1mutants, with simvastatin also fully rescuing their reduced quantal content. Thus, the further study of both compounds as potential ASD interventions is warranted.

2022-11-01·Basic & Clinical Pharmacology & Toxicology

The role of high‐conductance calcium‐activated potassium channel in headache and migraine pathophysiology

Review

作者: Al‐Karagholi, Mohammad Al‐Mahdi ; Hakbilen, Cemile Ceren ; Ashina, Messoud

AbstractMigraine is a common, neurovascular headache disorder with a complex molecular interplay. The involvement of ion channels in the pathogenesis of migraine gathered considerable attention with the findings that different ion channels subfamilies are expressed in trigeminovascular system, the physiological substrate of migraine pain, and several ion channel openers investigated in clinical trials with diverse primary endpoints caused headache as a frequent side effect. High‐conductance (big) calcium‐activated potassium (BKCa) channel is expressed in the cranial arteries and the trigeminal pain pathway. Recent clinical research revealed that infusion of BKCa channel opener MaxiPost caused vasodilation, headache and migraine attack. Thus, BKCa channel is involved in pathophysiological mechanisms underlying headache and migraine, and targeting BKCa channel presents a new potential strategy for migraine treatment.

100 项与 Flindokalner 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D04192	-	-	-

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
癫痫性脑病	临床前	英国	The University of Edinburgh	2023-08-30
癫痫性脑病	临床前	加拿大	University of Montréal	2023-08-30
缺血性卒中	临床前	美国	Bristol Myers Squibb Co.	2001-04-01
脑卒中	临床前	美国	Bristol Myers Squibb Co.	-

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临床结果

适应症

分期

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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


SFN2001	N/A	-	-	BMS-204352	鑰窪艱餘鏇壓艱壓鏇鑰(觸鏇壓憲窪築夢選糧齋) = 築壓獵遞積鬱製遞獵願簾艱膚餘膚齋淵簾淵積 (簾衊鹹製廠齋遞淵齋夢 )	-	2001-11-14