Development of a lasmiditan analogue for treatment of acute kidney injury

描述（申请人提供）：该项目的长期目标是开发一种安全有效的治疗性小分子，用于治疗急性肾损伤（阿基）。阿基由多种损伤引起，如败血症、缺血再灌注（I/R）或肾毒性暴露，近一半发生阿基的患者无法存活。由于治疗在很大程度上仍然是姑息性的，存活率几十年来保持不变，因此迫切需要新的治疗方法。线粒体功能障碍在阿基动物模型中的作用已得到验证，但尚未批准专门针对线粒体生物发生（MB）刺激线粒体功能和恢复肾功能的治疗药物。我们最近发表了一项使用？2-腺苷能受体激动剂福莫特罗证明了MB的刺激恢复了线粒体功能并加速了鼠模型中阿基的恢复（Jesinkey等人，2013-09-0952）。Lasmiditan是一种5-HT 1F受体激动剂，是一种新型甲基哌啶基苯甲酰胺，正在进行治疗偏头痛的II期临床试验。应注意的是，拉司米坦存在CNS相关不良事件。我们发现，拉西米坦也是肾近端小管细胞中MB的强效诱导剂。我们还鉴定了一种拉米替坦类似物（氮杂-拉米替坦），其中哌啶环被1，4-哌嗪环取代，这是一种同样有效的MB诱导剂。氮杂-拉希米坦是一种新的化学实体（NCE），未在拉希米坦物质组成专利中捕获。氮杂-拉米迪坦也是分2步合成的，与6步拉米迪坦合成相反。我们假设，刺激MB而CNS渗透有限的强效氮杂-拉咪坦类似物可用于治疗阿基。在目标1中，我们将合成30-50个氮杂-拉米替坦类似物，其将被修饰以保持MB活性，同时通过改变极性和/或连接可切割的肾靶向部分来减少CNS暴露。将在体外原代肾细胞试验中检测类似物的受体结合和MB活性。在目的2中，最初将特别强效和/或有效的结构多样的类似物静脉注射到小鼠中，以确定MB在肾脏和脑中的功效、血清半衰期和CNS浓度。在II期，将测试这些化合物在阿基的鼠模型中的功效。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a safe and efficacious therapeutic small molecule for treatment of acute kidney injury (AKI). AKI results from diverse insults such as sepsis, ischemia-reperfusion (I/R) or nephrotoxicant exposure and nearly half of those who develop AKI do not survive. Since treatment remains largely palliative and survival rates have remained unchanged for several decades, new therapeutic approaches are desperately needed. The role of mitochondrial dysfunction in animal models of AKI has been validated, but there is no approved therapeutic that specifically targets mitochondrial biogenesis (MB) to stimulate mitochondrial function and restore renal function. We have recently published a proof-of-principle study using the ?2-adendergic receptor agonist formoterol that demonstrates stimulation of MB restores mitochondrial function and accelerates recovery from AKI in a murine model (Jesinkey et al., JASN-2013-09-0952). Lasmiditan, a 5-HT1F receptor agonist, is a novel methylpiperidinyl- benzamide that is in phase II clinical trials for treatment f migraines. It should be noted that lasmiditan has CNS-related adverse events. We discovered that lasmiditan is also a potent inducer of MB in renal proximal tubular cells. We also identified an analogue of lasmiditan (aza-lasmiditan) in which the piperidine ring is replaced with a 1,4-piperazine ring that is an equally potent inducer of MB. Aza-lasmiditan is a new chemical entity (NCE) that is not captured in the lasmiditan composition of matter patents. Aza-lasmiditan is also synthesized in 2 steps, as opposed to the 6-step lasmiditan synthesis. We hypothesize that potent aza- lasmiditan analogues that stimulate MB with limited CNS penetration can be used to treat AKI. In Aim 1 we will synthesize 30-50 aza-lasmiditan analogues that will be modified to maintain MB activity while reducing CNS exposure via changes in polarity and/or attachment of cleavable renal-targeting moieties. The analogues will be tested for receptor binding and MB activity in an in vitro primary renal cell assay. In Aim 2 structurally diverse analogues that are particularly potent and/or efficacious will initially be injected i.v. into mice to determine MB efficacy in kidney and brain, serum half-life, and CNS concentrations In Phase II, these compounds will be tested for efficacy in murine models of AKI.