Kv7.2/7.3 Activators for the Treatment of Epilepsy Disorders

项目摘要 癫痫是已知的最古老和最常见的严重的慢性神经系统疾病，其特征是 反复发作。它目前影响着全球6500万人，其中包括230万成年人和近 美国有47万儿童。癫痫患者患有癫痫相关的残疾、抑郁 和焦虑症，并与一般人群相比增加了死亡率。在过去的几十年里， 在将新的抗癫痫药物推向市场方面做出了相当大的努力并取得了成功。尽管有空闲时间 在几种较新的药物中，大约30%的患者对治疗耐药。此外，反癫痫 药物治疗与严重的不良反应有关，通常需要仔细的滴定才能实现。 功效，同时最大限度地减少禁用副作用。 神经元钾通道在调节神经元活动中起着关键作用。Kv7.1-7.5通道为一个通道 电压门控性钾通道家族在维持兴奋性心肌细胞静息膜电位中的作用 细胞和神经元的KV7通道作用于抑制神经元的重复放电。对Kv7.2和 Kv7.3频道来自Kv7.2或Kv7.3基因突变的发现，这些基因与 一些遗传性癫痫。因此，激活Kv7.2和Kv7.3开放的小分子药物 通道具有治疗许多神经元过度兴奋性障碍的潜力，包括癫痫。 最近批准的抗癫痫药物ezogabine主要通过打开Kv7.2-7.5通道起作用，激活 GABAA系统也是如此。然而，除了耐受性问题外，使用ezogabine还与 严重的不良反应限制了它的应用，包括视网膜和皮肤变色，这可能与 与伊佐加宾的化学不稳定性有关，而不是它的KV7活性。 Knopp生物科学计划的目标是设计和开发一个Kv7.2/7.3激活剂，完全实现 这一目标在解决难治性癫痫患者未得到满足的医疗需求方面的潜力 难以治疗的全身性癫痫综合征。这样的化合物将具有显著改善的 与ezogabine相比，耐受性和安全性不仅通过改善固有化学稳定性 特点，但也由于Kv7.4活性降低，以避免可能引起的副作用 开放Kv7.4通道存在于血管和平滑肌中。此外，下一代 Kv7.2/7.3激活器将移除GABAA通道上的活动。为了做到这一点，克诺普开发了一种 利用表达KV7的细胞系和原代神经元进行多种体外筛选试验。这些数据，以及 用一组体外测试产生的新陈代谢和类似药物的特性，将是 用于筛选在急性和慢性癫痫动物模型中研究的化合物。我们还将评估 化合物在动物体内的耐受性，以确定显示最佳治疗窗口的候选药物 药效好，副作用小。

Project Summary Epilepsy is the oldest known and most common serious, chronic neurological disorder that is characterized by recurrent seizures. It currently affects 65 million people worldwide, including 2.3 million adults and nearly 470,000 children in the United States. People with epilepsy suffer from seizure-related disabilities, depression and anxiety and have increased mortality compared to the general population. Over the last few decades there has been considerable effort and success to bringing new anti-seizure drugs to market. Despite the availability of several newer medications, approximately 30% of patients are treatment-resistant. Furthermore, anti-seizure drug therapies are associated with significant adverse effects and often require careful titration to achieve efficacy while minimizing disabling side effects. Neuronal potassium channels play a key role in regulating neuronal activities. Kv7.1-7.5 channels are one family of voltage-gated potassium channels critical in maintaining the resting membrane potential of excitable cells and neuronal Kv7 channels act to dampen repetitive firing of neurons. Additional interest in Kv7.2 and Kv7.3 channels come from the discovery of mutations in the Kv7.2 or Kv7.3 genes found to be associated with some inherited forms of epilepsy. Thus small molecule drugs that activate the opening of Kv7.2 and Kv7.3 channels have potential to treat many neuronal hyperexcitability disorders, including epilepsy. A recently approved anti-seizure drug, ezogabine, acts primarily by opening Kv7.2-7.5 channels with activity on the GABAA system as well. However, in addition to tolerability issues, ezogabine use has been associated with serious adverse effects that have limited its utility, including retinal and skin discoloration that are likely linked to ezogabine’s chemical instability rather than its Kv7 activities. The goal of this Knopp Biosciences program is to design and develop a Kv7.2/7.3 activator that fully realizes the potential of this target to address the unmet medical need of treatment-resistant epilepsy patients and difficult-to-treat generalized epilepsy syndromes. Such a compound will possess a dramatically improved tolerability and safety profile over that of ezogabine not only via improved intrinsic chemical stability characteristics, but also due to reduced Kv7.4 activity so as to avoid side effects that may be caused by opening Kv7.4 channels present in blood vessels and smooth muscle. In addition, the next generation Kv7.2/7.3 activator will remove activity on the GABAA channels. To accomplish this, Knopp has developed a variety of in vitro screening assays using Kv7-expressing cell lines and primary neurons. These data, along with those generated from a battery of in vitro assays testing for metabolism and drug-like properties, will be used to select compounds for study in acute and chronic animal models of epilepsy. We will also evaluate the tolerability of compounds in animals to identify drug candidates that show the best therapeutic window for efficacy with minimal side effects.