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慢性神经系统疾病，其特征在于 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。癫痫患者患有与癫痫有关的残疾，抑郁症 和焦虑，与普通人群相比，死亡率增加。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巨大的成功。尽管有 在几种较新的药物中，大约30%的患者对治疗有抗药性。此外，防癫痫 药物治疗与显著的副作用有关， 有效性，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关键作用。Kv7.1-7.5通道是一个 电压门控钾通道家族，在维持可兴奋的静息膜电位中起关键作用 细胞和神经元Kv 7通道用于抑制神经元的重复放电。对Kv7.2的额外兴趣， Kv7.3通道来自于发现与以下疾病相关的Kv7.2或Kv7.3基因中的突变： 一些遗传性癫痫因此，激活Kv7.2和Kv7.3开放的小分子药物 通道具有治疗包括癫痫在内的许多神经元过度兴奋性疾病的潜力。 最近批准的抗癫痫药物依佐加滨主要通过打开Kv7.2-7.5通道起作用， GABAA系统也是如此。然而，除了耐受性问题外，依佐加滨的使用还与 严重的不良反应限制了其效用，包括视网膜和皮肤变色，这可能与 与依佐加宾的化学不稳定性有关，而不是其Kv 7活性。 该Knopp Biosciences计划的目标是设计和开发一种Kv7.2/7.3激活剂， 这一目标解决难治性癫痫患者未满足的医疗需求的潜力， 难以治疗的全身性癫痫综合征。这种化合物将具有显著改善的 不仅通过改善的内在化学稳定性， 这不仅是由于Kv7.4活性降低，而且还由于Kv7.4活性降低，从而避免了可能由Kv7.4引起的副作用。 打开血管和平滑肌中的Kv7.4通道。此外，下一代 Kv7.2/7.3激活剂将去除GABAA通道上的活性。为了实现这一目标，Knopp开发了一种 使用表达Kv 7的细胞系和原代神经元的各种体外筛选测定。这些数据，沿着 与那些从一组体外试验中产生的代谢和药物样特性测试，将是 用于选择用于急性和慢性癫痫动物模型研究的化合物。我们还将评估 化合物在动物中的耐受性，以鉴定显示最佳治疗窗口的候选药物， 副作用最小的功效。

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.