Identification of analogs that improve activity towards opened KV7.2/3-channels while reducing adverse effects on liver cells in vitro

结构上相关的钾通道调节剂氟平和雷替加宾最近因不良副作用而从市场上召回。毒性的原因很可能是由于这两种药物被氧化成活性代谢物，在氟平汀的情况下，这可能会导致肝脏损害，而在瑞格他滨的情况下，会与内源性黑色素反应，在眼睛和手指指甲组织中形成蓝色色素。在上一次的资助中，我们开发了氟平和雷替加宾的类似物，通过氮原子交换硫原子，得到的类似物要么被氧化成不起反应的亚砜和亚砜，要么完全不被氧化。这些类似物的优点是它们不会被生物转化为有毒的氮喹酮二亚胺代谢物；因此，既不会与蛋白质反应形成可能导致肝脏毒性的免疫原性半抗原，也不会导致有色色素的形成。同时，许多新合成的类似物在打开异四聚体Kv7.2/3通道方面显示出更好的效力。因此，它们的剂量可能比最初的止痛药氟平或抗癫痫药物雷替加宾低得多，后者在从市场上撤下后，打开了一个空白的治疗利基市场。该项目的主要目标是在旨在提高这类独特药物的治疗潜力的合成和筛选的迭代过程中，探索新的钾通道调节剂在通道开放活性和毒性方面的生物活性。此外，我们希望探索一个未经证实的假设，即氮原子与硫原子的交换可以导致有利的氧化抑制或代谢转换到毒性较低的产品。进一步，重要的是通过测定化合物在其他离子通道上的活性来评估化合物对Kv7.2/3的选择性。这也可能导致发现具有独特不同选择性模式的新的铅结构。此外，氧化性能不仅应该像我们过去所做的那样用电化学方法来评估，而且应该更紧密地与生物系统结合，以便更好地预测活性代谢物的潜在形成。这些研究还将有助于优化新化合物的药代动力学性质，例如关于血浆半衰期。由于最活跃的化合物本质上是亲脂性的，该项目还将致力于改善物理化学性质，如水的溶解度。为了实现这一目标，将探索先前项目中由于时间限制而无法进行的进一步结构修改。该项目旨在为开发具有良好GI谱、低成瘾潜力和低肝毒性的新型止痛药做出贡献。

The structurally related potassium channel modulators flupirtine and retigabine were recalled recently from the market due to undesirable side effects. The cause for toxicity is likely to be due to the oxidation of both drugs to reactive metabolites, which in the case of flupirtine can cause liver damage and in the case of retigabine can react with endogenic melanin to form blue pigments in the eye and finger nail tissues. In the previous grant, we developed analogues of both flupirtine and retigabine, whereby a nitrogen was exchanged for a sulfur atom, resulting in analogues that are oxidized either to unreactive sulfoxides and sulfones or are inert to oxidations altogether. These analogues could offer the advantage that they will not be biotransformed to toxic azaquinonediimines metabolites; thus, neither reactions with proteins to form immunogenic haptens that could cause hepatotoxicity, nor reactions leading to the formation of color pigments are feared. At the same time, many of the newly synthesized analogues showed much improved potency with regards to opening of the heterotetrameric Kv7.2/3 channel. Thus, they could possibly be dosed at much lower levels than the original analgesic drug flupirtine or the antiepileptic drug retigabine, which after their removal from the market opened a vacant therapeutic niche. The main goal of the project is to explore the biological activities of new potassium channel modulators with respect to channel opening activity and toxicity in an iterative process of synthesis and screening aimed at improving the therapeutic potential of this unique class of drugs. Moreover, we wish to explore the unproven hypothesis that exchange of the nitrogen atoms for sulfur atom can result in an advantageous inhibition of oxidation or a metabolic switching to less toxic products.Moving forward it is important to assess the selectivity of the compounds for Kv7.2/3 by determining the activity on other ion channels. This could also lead to the discovery of new lead structures with uniquely different selectivity patterns. Furthermore, the oxidation properties should not only be evaluated with electrochemical methods, as we have done in the past, but more closely with biological systems so that the potential formation of reactive metabolites can be better anticipated. These studies will also serve to optimize the pharmacokinetic properties of the new compounds, e.g., with regards to plasma half-life.Since the most active compounds are lipophilic in nature, the project will also aim to improve the physicochemical properties, such as water solubility. Towards this goal, further structural modifications will be explored that were not possible because of time constraints in the previous project.The project aims to contribute to the development of novel analgesics with good GI profiles, low addiction potential and low hepatotoxicity.