Small conductance Ca²⁺-activated K⁺ (SK) channels, expressed throughout the CNS, are comprised of SK1, SK2 and SK3 subunits, assembled as homotetrameric or heterotetrameric proteins. SK channels expressed somatically modulate the excitability of neurons by mediating the medium component of the afterhyperpolarization. Synaptic SK channels shape excitatory postsynaptic potentials and synaptic plasticity. Such SK-mediated effects on neuronal excitability and activity-dependent synaptic strength likely underlie the modulatory influence of SK channels on memory encoding. Converging evidence indicates that several forms of long-term memory are facilitated by administration of the SK channel blocker, apamin, and impaired by administration of the pan-SK channel activator, 1-EBIO, or by overexpression of the SK2 subunit. The selective knockdown of dendritic SK2 subunits facilitates memory to a similar extent as that observed after systemic apamin. SK1 subunits co-assemble with SK2; yet the functional significance of SK1 has not been clearly defined. Here, we examined the effects of GW542573X, a drug that activates SK1 containing SK channels, as well as SK2/3, on several forms of long-term memory in male C57BL/6J mice. Our results indicate that pre-training, but not post-training, systemic GW542573X impaired object memory and fear memory in mice tested 24 h after training. Pre-training direct bilateral infusion of GW542573X into the CA1 of hippocampus impaired object memory encoding. These data suggest that systemic GW542573X impairs long-term memory. These results add to growing evidence that SK2 subunit-, and SK1 subunit-, containing SK channels can regulate behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.

2020-10-01·Journal of Molecular and Cellular Cardiology2区 · 医学

In vivo knockdown of SK3 channels using antisense oligonucleotides protects against atrial fibrillation in rats

2区 · 医学

Article

作者: Kim Boddum ; Thomas Jespersen ; Arnela Saljic ; Luca Soattin ; Dagmar S. Trachsel

INTRODUCTIONGapmeRs are oligonucleotides that bind to a specific RNA sequence and thereby affecting posttranscriptional gene regulation. They therefore hold the potential to manipulate targets where current pharmacological modulators are inefficient or exhibit adverse side effects. Here, we show that a treatment with a GapmeR, mediating knockdown of small conductance Ca²⁺-activated K⁺ channels (SK3), has an in vivo protective effect against atrial fibrillation (AF) in rats.MATERIAL AND METHODSA unique SK3-GapmeR design was selected after thorough in vitro evaluation. 22 rats were randomly assigned to receive either 50 mg/kg SK3-GapmeR or vehicle subcutaneously once a week for two weeks. Langendorff experiments were performed seven days after the last injection, where action potential duration (APD₉₀), effective refractory period (ERP) and AF propensity were investigated. SK3 channel activity was evaluated using the SK channel blocker, ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine). SK3 protein expression was assessed by Western Blot.RESULTSThe designed GapmeR effectively down-regulate the SK3 protein expression in the heart (48% downregulation, p = 0.0095) and did indeed protect against AF. Duration of AF episodes elicited by burst pacing in the rats treated with SK3-GapmeR was reduced 78% compared to controls (3.7 s vs. 16.8 s, p = 0.0353). The number of spontaneous AF episodes were decreased by 68% in the SK3-GapmeR group (39 episodes versus 123 in the control group, respectively) and were also significantly shorter in duration (7.2 s versus 29.7 s in the control group, p = 0.0327). Refractoriness was not altered at sinus rhythm, but ERP prolongation following ICA application was blunted in the SK3-GapmeR group.CONCLUSIONThe selected GapmeR silenced the cardiac SK3 channels, thereby preventing AF in rats. Thus, GapmeR technology can be applied as an experimental tool of downregulation of cardiac proteins and could potentially offer a novel modality for treatment of cardiac diseases.

2016-11-01·Pflügers Archiv - European Journal of Physiology4区 · 医学

Antiarrhythmic effect of the Ca2+-activated K+ (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation

4区 · 医学

Article

作者: Jespersen, Thomas ; Grunnet, Morten ; Kirchhoff, Jeppe Egedal ; Sheykhzade, Majid ; Abildgaard, Lea ; Diness, Jonas Goldin

Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca²⁺-activated K⁺ (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.

项与 NSD-8011 相关的新闻（医药）

2023-05-15

·Outsourcing Pharma

Drug to treat atrial fibrillation without safety issues being developed by Acesion Pharma

Acesion Pharma announced positive pre-clinical data for AP31969 today (May 15) and said its second-generation oral SK channel inhibitor was developed for chronic oral maintenance treatment to prevent AF recurrence. The company said it aims to develop a novel drug for AF that solves the major concern with existing drugs; a high-risk of life-threatening cardiac arrhythmia, also known as proarrhythmia. It said that to refine drug proarrhythmia risk prediction; regulators, academics, and industry have collaborated on developing pre-clinical models with this specific purpose. AF is the most common type of treated heart arrhythmia - when the heart beats too slowly, too fast, or in an irregular way. When a person has AF, the normal beating in the upper chambers of the heart - the two atria is irregular, and blood doesn’t flow as well as it should from the atria to the lower chambers of the heart - the two ventricles. AFib may happen in brief episodes, or it may be a permanent condition. It was reported that in two such models, AP31969 has demonstrated a low risk of proarrhythmia with robust differentiation to existing drugs, which have a high risk of proarrhythmia, tested in the same models. Further results from pre-clinical studies, Acesion said, showed that AP31969, tested at expected supratherapeutic doses across two in-vivo large animal models, has no prolongations of the corrected QT interval, a well-established marker of proarrhythmia risk. The researchers said that in addition to its promising cardiac safety profile, AP31969 has demonstrated good oral pharmacokinetic properties across different animal species and a low-risk of causing drug-drug interactions, another significant issue with existing drugs. googletag.cmd.push(function () { googletag.display('text-ad1'); }); AP30663, Acesion’s first-in-class SK ion channel inhibitor for conversion of AF to normal sinus rhythm, recently demonstrated robust efficacy in patients with AF. AP31969 has shown strong and similar efficacy to AP30663 in two animal models, supporting that efficacy can be expected to be shared across the two compounds. Finally, AP31969 has recently completed the toxicology studies required by regulatory authorities, ahead of the phase 1 trial which Acesion plans to start in H2 2023. Anders Gaarsdal Holst, chief executive officer of Acesion, said: “With a growing number of patients suffering from atrial fibrillation, there is a significant need for treatment. Unfortunately, all existing drugs have major safety issues that endanger patients. “Acesion’s positive pre-clinical results support that AP31969 has the potential to solve these issues and greatly broaden the use of pharmacological treatment within atrial fibrillation. We are excited to continue the development of AP31969 with a phase 1 clinical trial and look forward to the continued progress we will make in the coming year.” The company said that pre-clinical studies have shown pronounced antiarrhythmic effects in the atria while avoiding effects on the ventricles, the major chambers of the heart and the source of most safety issues with existing drugs, when inhibiting the SK channels. Further, it said, the SK channel has strong genetic validation with genes encoding the SK channels having one of the strongest associations to AF in human genome-wide association studies.

临床1期AHA会议

2023-03-24

·CPHI制药在线

结核防治日 | 谈谈抗结核药物靶点研究新进展

关注并星标CPHI制药在线今年3月24日是第28个世界防治结核病日，今年的主题是："你我共同努力终结结核流行"。结核病（tuberculosis，TB）是由结核分枝杆菌（mycobacterium tuberculosis，MTB）引起的一种慢性致死性疾病，近些年来，由于抗结核药物的大量使用，抗结核作用位点的突变，耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）成为控制和治疗结核病的重大挑战。链霉素(streptomycin，SM)和对氨基水杨酸(p-amino salicylic acid，PAS) 是最早被发现并用于治疗TB的药物。随后，异烟肼(INH)的出现形成了" INH+SM+PAS"的三联疗法，基于患者的药源和耐受性，其中的PAS可选用氨硫脲(TB1)或乙胺丁醇(EMB)替换。1965年利福平(RIF)开始应用于临床后，相关研究发现"INH+RIF"可将治疗疗程减短到9个月，再进一步与吡嗪酰胺(PZA)结合使用能够使疗程减短至半年。此后，相关研究一直没有研发出应用于TB治疗的全新结构药物。近几十年来仅有强生公司的新型结核分枝杆菌ATP合酶抑制剂贝达喹啉（bedaquiline）和日本大冢公司的德拉马尼（delamanid）两种抗结核药物被批准上市，而目前已有耐药菌株出现及引起副作用的报道。因此，寻找新的抗结核药物作用靶点，开发新型抗结核药物迫在眉睫。（相关阅读：《新型抗结核药物的研究进展》）结核病的防治和新药研发首先需要发现和阐明其致病菌关键生理活动的分子机制。其中，结核分枝杆菌的细胞壁合成过程、DNA/RNA合成和能量代谢过程被认为是理想突破口，许多抗结核药物和在研药物均作用于这些重要生理途径。与细胞壁有关的药物靶点结核杆菌的细胞壁具有独特的结构和组成，是病原体抵抗环境压力，免受抗生素杀伤和逃避宿主免疫反应的天然屏障。其结构和组成与革兰氏阳性/阴性细菌以及真菌都存在显著差异，结核分枝杆菌细胞壁组分肽聚糖(peptidoglycan, PG)、阿拉伯半乳聚糖(arabinogalactan, AG)、分枝菌酸(mycolic acid, MA)、脂阿拉伯甘露聚糖(lipoarabinomannan,LAM)等均是结构复杂的分子，其合成、运输、组装、调控等需要一系列酶和转运膜蛋白参与完成。破坏细胞壁的完整性不仅有助于杀菌药物的进入，还会严重地影响病原体的生存，故细胞壁合成通路中的关键蛋白被公认为是很好的药物靶标。 ①DprE(decaprenylphosphoryl-D-ribose 2'-epimerase)。DprE是由DprE1和DprE2构成的异二聚体，在D-核糖向D-阿拉伯呋喃糖(DPA)的转化中起重要作用，而DPA是合成细胞壁阿拉伯聚糖的唯一前体。目前研发的抑制剂主要针对DprE1，包括苯并噻嗪酮类、氟喹诺酮类和氮杂吲哚类，其中氮杂吲哚衍生物TBA-7371处于临床试验的第一阶段。 ②分枝杆菌膜蛋3(Mmp L3)。Mmp L3主要参与Mtb的脂质运输、聚合和机体免疫调节等功能，是近期发现的一类治疗药物靶点。到目前为止，大约有8类不同分子构型的具有抗菌活性的MmpL3抑制剂被发现，其中乙二胺类的SQ109已处于2b-3期临床试验阶段。该小分子对耐药菌株有很好的杀菌效果，具有极低的耐药突变率，有望成为新的抗结核治疗药物。 ③L-鼠李糖合成相关酶。L-鼠李糖连接细胞壁肽聚糖和阿拉伯半乳聚糖（AG）两种组分，通过抑制其合成，可以影响MTB细胞壁的正常合成及生存。由于人体内不存在L-鼠李糖，所以L-鼠李糖合成中相关酶可以作为具有较好选择性的药物靶点。L-鼠李糖的合成主要涉及4种酶促反应，参与反应的4种酶分别为葡萄糖-1-磷酸脱氧胸苷转移酶（RmlA）、dTDP-D-葡萄糖-4,6-脱水酶（RmlB）、dTDP-4-酮基-6-脱氧葡萄糖差向异构酶（RmlC）和 dTDP-4-酮-鼠李糖还原酶（RmlD）。其中Rml C因其结构的特殊和底物的高特异性，以及对辅酶因子无依赖性而在研究领域受到广泛关注，但目前尚无相关的抑制剂上市。 ④阿拉伯糖基转移酶。细胞壁阿拉伯糖基转移酶EmbA、EmbB和EmbC均是参与细胞壁阿拉伯聚糖合成的阿拉伯糖基转移酶，属于糖基转移酶超家族GT-C中的GT-53家族。其中，EmbA和EmbB参与阿拉伯半乳聚糖AG的合成，而EmbC参与脂阿拉伯甘露聚糖LAM的合成。Emb蛋白均是利用D-阿拉伯呋喃糖(DPA)作为阿拉伯糖供体，将阿拉伯单糖转移至特定的阿拉伯聚糖受体上，完成阿拉伯聚糖的延伸或者分枝。Emb蛋白的活性测试表明，乙胺丁醇可以抑制其活性，因而是这些蛋白的直接作用靶点。研究表明，结核杆菌中的Emb蛋白均是无法敲除的关键蛋白，而一线药物乙胺丁醇的临床耐药突变大多发生在Emb蛋白上，尤其集中在EmbB蛋白。 ⑤烯酰基载体蛋白还原酶。烯酰基载体蛋白还原酶(Inh A)在细胞壁脂肪酸合成方面发挥着重要作用，是一线药物异烟肼(INH)的一个关键作用靶点。INH属于一类前体药物，依赖于KatG酶将其激活，而KatG的基因突变会阻断该激活途径并导致耐药。因此现在许多研究聚焦于Inh A的"直接抑制剂"。三氯生(TCS)属于一类广谱抗生素，可对Inh A造成可逆、温和的抑制。 ⑥D-丙氨酸-D-丙氨酸连接酶A(D-Alanyl-D-alanine ligase A，DdlA)能在ATP的介导下促进D-丙氨酸(Ala)分子的二聚化，获得D-丙氨酰-D-Ala。其产物与肽聚糖(PG)的五肽生物合成相关，能显著影响Mtb细胞壁的正常功能。D-环丝氨酸(DCS)是DdlA的抑制剂，可抑制菌株的生长。 ⑦HspX蛋白。研究发现，在宿主巨噬细胞中，低氧水平会诱导分枝杆菌细胞壁中的HspX高度表达，表明它在TB感染的潜伏期中起着重要作用。由于治疗期间人体容易产生抗生素耐药性，因此通过接种疫苗进行早期预防是控制感染的有效途径之一。卡介苗(Bacillus calmette-guerin，BCG)是目前可用的唯一结核病疫苗。有学者通过编码融合HspX-PPE44-EsxV抗原，得到了一种新型DNA疫苗，并在BALB/c小鼠感染模型中测试，结果表明，HspX融合疫苗可以在小鼠体内诱导高水平的特定细胞因子，而且在BCG增强免疫方案中使用该DNA疫苗可产生大量的IFN-γ、IL-12和TGF-β等细胞因子，从而取得更好的疗效。与DNA/RNA 合成有关的药物靶点 ①DNA回旋酶。DNA回旋酶由两个亚蛋白单元A（GyrA）和 B（GyrB）以异源四聚体的形式存在，DNA回旋酶在人体内不存在，但却是细菌生存的必需物质，抑制其作用可导致细菌死亡。氧氟沙星、左氧氟沙星和莫西沙星等喹诺酮类抗结核药物主要作用于结核分枝杆菌GyrA蛋白，阻止DNA 的复制和转录，从而杀死MTB。近年来，由于GyrA亚基易发生氟喹诺酮类耐药突变，药物研究及靶点筛选已转向GyrB亚基，相继出现了一些以GyrB 为靶点的药物，如苯并咪唑、尿素酶等。 ②RNA 聚合酶。RNA聚合酶在Mtb和真核生物中的结构存在一定差别。抗生素利福平(RIF)对快速增殖期和间断繁殖的Mtb 杀菌力都很强，与链霉素和异烟肼联用时可使它们的治疗效果增强RIF耐药性的产生主要是由 RNA 聚合酶 β 亚基的 rpoB 基因突变所致。 ③次黄嘌呤鸟嘌呤磷酸核糖转移酶。次黄嘌呤鸟嘌呤磷酸核糖转移酶（HGPRT）是一种细胞质酶，在体内广泛存在，它不仅参与嘌呤碱基的补救合成途径，对 DNA/RNA 的合成起重要作用，而且关系到嘌呤类药物的代谢，是调控该类药物药理效应和毒性反应的关键酶，两种吡咯烷核苷磷酸盐是目前针对Mtb-HGPRT最有效的抑制剂。 ④胸苷酸激酶。胸苷酸激酶(TMK)是一种核苷单磷酸激酶，在嘧啶合成中起关键作用，对细菌的DNA合成至关重要。TMK可催化ATP和脱氧胸苷-5'-单磷酸(dTMP)之间的可逆磷酸化，产生ADP和脱氧胸苷-5'-二磷酸(dTDP)，并通过再次磷酸化得到胸苷5'-三磷酸(dTTP)。Mtb-TMK在人体中的低同源性使其成为潜在的药物靶点。通过高通量筛选和核磁共振的方法，发现了两类新型 TMK抑制剂，分别是氰基吡啶酮类和萘啶类。以往的TMK 抑制剂都是胸苷单磷酸类似物或者是含有胸苷单磷酸结构，而这两类化合物是非胸腺嘧啶核苷类 TMK抑制剂，对TMK具有较好的选择性。与能量代谢有关的药物靶点在近年的研究中，针对结核分枝杆菌能量代谢系统，特别是氧化磷酸化途径的靶标研究已成为研究者关注的热点。虽然病原菌的有氧呼吸与真核生物类似，都依赖于一系列蛋白质复合体，包括NADH、琥珀酸、细胞色素c氧化还原酶和ATP合成酶，但是其结构和组装形式与真核线粒体和革兰氏阳性/阴性细菌均存在显著差异，其独特的特点使相关复合物成为理想的药物靶点。 ①ATP合成酶。Mtb中的ATP合酶是一种含有多个亚基的跨膜蛋白复合物，参与几乎所有活细胞的能量代谢和部分细胞间的信号传递。由atpE基因编码的ATP合酶C亚基是抑制剂贝达喹啉的主要作用靶点。但基因突变导致的贝达喹啉耐受加上贝达喹啉所导致的心律失常及恶心、头痛一系列副作用，限制了其临床应用。对一系列双喹啉衍生物评估发现，贝达喹啉SAR衍生的TBAJ-587和TBAJ-876化合物在体外和小鼠结核病模型研究中均显示出其对TB的潜在疗效，目前两类化合物皆处于临床研究的第一阶段。 ②细胞色素bc1: aa3。Mtb的细胞色素bc1: aa3是由甲萘醌、细胞色素c、还原酶(bc1)和细胞色素aa3型氧化酶组成的复合体，主要在呼吸链中发挥电子传递效能，显著影响ATP的合成。咪唑并[1, 2-α]吡啶类化合物Q203是针对细胞色素bc1: aa3复合体中细胞色素b亚基 (the cytochrome b subunit， QcrB)而研发的抑制剂，目前处于临床研究的第二阶段。 ③莽草酸激酶。莽草酸途径的终产物是分支酸盐，是一种芳香族氨基酸和甲基萘醌等物质的前体。在该途径中起关键作用的是莽草酸激酶 (shikimate kinase，SK)，该途径只存在于细菌、真菌、藻类和植物中，人体内不存在该途径，所以此途径中的关键酶可以作为抗结核靶点。目前对SK 的研究大多数停留在通过计算机辅助药物设计，对天然底物进行结构改造指导合成底物类似物阶段，但合成的化合物与SK 的亲和力往往较好，也预示了SK作为抗结核药物靶点的广阔前景。 ④细胞色素P450酶系。细胞色素P450 (cytochromeP450， CYPs) 是一类具有混合功能的氧化还原酶，在细胞合成与分解代谢活动中发挥关键作用。许多细菌P450 酶系的酶不超过5种，大肠杆菌中甚至没有P450 酶系，而在MTB中P450 酶系却含有20 多种酶，表明其在MTB代谢中发挥着重要的作用，也表明其中的一些酶很有可能成为新的抗结核药物靶点。近年来，对MTB中P450 酶系CYP51、CYP121和CYP141的研究较多。氯法齐明(Cfz)被视作核心二线药物，体外鉴定结果显示其可有效抑制CYPs。近年来，随着科学技术的进步和研究水平的提高，结核杆菌在分子水平上的生理功能得以精确阐释，多个药物和候选化合物的靶向作用机制得到了详细的阐明，相关的结合位点及其结合方式为新型抗结核小分子的开发提供了非常有价值的信息。相信不久的将来，对于这些靶点的新药开发一定会取得重要突破。参考资料 [1]吴疆,崔嘉伟,薛云新,王岱.抗结核药物靶点的研究进展[J].中国抗生素杂志,2022,47(11):1119-1127.DOI:10.13461/j.cnki.cja.007423. [2]王霞,朱宁屿,姜威,司书毅.抗结核药物靶点的研究进展[J].中国医药生物技术,2018,13(03):259-264. [3]陈晓博,李俊.抗结核药物靶点的结构研究进展[J].自然杂志,2021,43(05):335-342. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

上市批准

2023-03-19

·Outsourcing Pharma

Acesion's positive trial data for treatment of atrial fibrillation

Acesion Pharma carried out the trial to evaluate AP30663, the inhibitor for conversion of AF to normal sinus rhythm. The trial enrolled 63 patients with a current episode of AF and tested two intravenous doses of AP30663 at 3mg and 5mg/kg compared to placebo. The primary endpoint was the proportion of patients with AF conversion to sinus rhythm within 90 minutes of infusion start. The proportion (conversion rate) for AP30663 5 mg/kg exceeded 50% with no conversions observed for placebo and with a numerical dose-response between the 3 and 5 mg/kg dose. The trial employed a Bayesian analysis (used to update the probability for a hypothesis as more evidence or information becomes available) and found a posterior probability of more than 99.9% of a true AF conversion rate, greater than placebo for each of the two doses. Anders Gaarsdal Holst, chief executive officer of Acesion, said: “This clinical trial has proven the general mechanism of action of SK channel inhibition for treatment of Atrial Fibrillation. It further de-risks our pipeline of small molecule SK inhibitors, including AP31969, our ongoing second-generation oral lead program, which targets the much broader and chronic treatment indication of sinus rhythm maintenance, and which is planned to start phase 1 in the second half of 2023.” The results from this analysis were supported by a traditional analysis of the primary endpoint, demonstrating highly significant P-values (probability of obtaining results) for each of the two doses compared to placebo. googletag.cmd.push(function () { googletag.display('text-ad1'); }); The safety profile was consistent with observations found in two previous phase 1 trials with AP30663. The treatment was well tolerated, with no serious adverse events (AEs) reported in the AP30663 groups. The main safety concern with currently available AF drugs - ventricular arrhythmias -, were not seen in the trial. Jørgen Søberg Petersen, chairman of the board of directors and partner at Novo Holdings A/S, said: “With these impressive, first-in-class, clinical proof-of-concept data, we are very excited to see the pioneering efforts of Acesion coming to fruition. With clinical proof-of-concept data on the first-generation molecule, Acesion has significantly de-risked their SK channel inhibitor program and we see a great potential for this novel class of compounds for the treatment of chronic AF.” A transient increase in the echocardiogram (ECG) QTc interval compared to placebo was seen with both doses. This increase in QT interval (a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart) was less than, or comparable to, what is seen with some currently available drugs. Based on non-clinical studies with AP30663, as well as human genetic data, the QT effect can be ascribed to a compound-specific off-target inhibition of the human ether-à-go-go-related gene (hERG) ion channel. Acesion is advancing an oral SK channel inhibitor program for chronic maintenance treatment to prevent AF recurrence, using a 2nd generation molecule with higher specificity that avoids ventricular effects, including hERG channel inhibition, while maintaining efficacy in preclinical models. AF is the most common type of cardiac arrhythmia and is forecast to affect 24 million people in the US and EU by 2030. Acesion is advancing the first new approach to treating AF for decades. It has a pipeline of novel, first-in-class, orally available, small molecules that inhibit the SK channels. In pre-clinical studies, inhibiting the SK channels has been shown to result in pronounced antiarrhythmic effects in the atria while avoiding effects on the ventricles, the major chambers of the heart. Furthermore, the SK channel has strong genetic validation, with genes encoding the SK channels having one of the strongest associations to AF in human genome-wide association studies. A. John Camm emeritus professor of clinical cardiology, St. George’s University of London , said: “With the numbers suffering from Atrial Fibrillation forecast to grow dramatically in the coming years, and with the many safety issues associated with currently available drugs, there is a great unmet need for safer AF treatments that can decrease the risk for patients, but also remove barriers for physicians wanting to keep their patients in sinus rhythm by treating them with an antiarrhythmic drug. This novel mechanism holds the promise to deliver on these aspects.” Acesion builds on 20 years of know-how with development of small-molecule SK inhibitors and is the world leader in the field of SK channel inhibition, being the only company able to identify and progress SK channel inhibitors into clinical trials.

临床结果临床1期

100 项与 NSD-8011 相关的药物交易

登录后查看更多信息