Development of a lasmiditan analogue for treatment of acute kidney injury

开发用于治疗急性肾损伤的 lasmiditan 类似物

• 批准号: 8781967
• 负责人: Craig Cano Beeson
• 金额: $ 23.29万
• 依托单位: MITOHEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781967
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adverse event; Affinity; Agonist; Animal Model; Arts; Benzamides; Biogenesis; Biological Assay; Blood specimen; Brain; C57BL/6 Mouse; Cells; Chemicals; Clinical Treatment; Development; Drug or chemical Tissue Distribution; Goals; Half-Life; Harvest; Homology Modeling; Human; Immunoblotting; In Vitro; Ischemia; Kidney; Lead; Legal patent; Life; Metabolic; Migraine; Mitochondria; Mitochondrial DNA; Modeling; Modification; Mus; Organ; Penetration; Peripheral; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Piperazines; Process; Publishing; Recovery; Renal function; Reperfusion Therapy; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Sampling; Sepsis; Serum; Structure; Survival Rate; Tail; Testing; Therapeutic; Tissues; Tubular formation; Veins; alkalinity; analog; design; efficacy testing; formoterol; functional restoration; improved; in vivo; kidney cell; meetings; mitochondrial dysfunction; novel; novel therapeutic intervention; palliative; phase 1 study; phase 2 study; piperidine; preclinical study; public health relevance; receptor; receptor binding; small molecule

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.

项目描述（由申请人提供）：该项目的长期目标是开发一种安全有效的治疗急性肾损伤（AKI）的小分子药物。AKI由多种损伤引起，如败血症、缺血再灌注（I/R）或肾毒物暴露，近一半的AKI患者无法存活。由于治疗在很大程度上仍然是姑息性的，几十年来生存率保持不变，迫切需要新的治疗方法。线粒体功能障碍在AKI动物模型中的作用已经得到证实，但目前还没有批准的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方法。我们最近发表了一项原理验证研究，使用？2-腺能受体激动剂福莫特罗在小鼠模型中显示刺激MB可恢复线粒体功能并加速AKI的恢复（Jesinkey等，JASN-2013-09-0952）。Lasmiditan是一种5-HT1F受体激动剂，是一种用于治疗偏头痛的II期临床试验的新型甲基哌啶基苯甲酰胺。值得注意的是，拉西米坦有中枢神经系统相关的不良事件。我们发现拉斯米坦在肾近端小管细胞中也是一种有效的MB诱导剂。我们还发现了一种类似于拉斯米坦的物质（aza-lasmiditan），其中哌啶环被一个同样有效的MB诱导剂1,4-哌嗪环取代。aza-lasmiditan是一种新的化学实体（NCE），在物质专利的拉斯米坦组合物中不被捕获。Aza-lasmiditan也是2步合成，而不是6步合成lasmiditan。我们假设，有效的阿扎拉西坦类似物刺激MB，有限的中枢神经系统渗透可用于治疗AKI。在Aim 1中，我们将合成30-50个aza-lasmiditan类似物，这些类似物将被修饰以保持MB活性，同时通过改变可切割肾靶向部分的极性和/或附着来减少CNS暴露。这些类似物将在体外原代肾细胞试验中测试受体结合和MB活性。在第二期研究中，研究人员首先将结构多样的强效和/或有效的类似物静脉注射到小鼠体内，以确定MB在肾脏和大脑中的疗效、血清半衰期和中枢神经系统浓度。在第二期研究中，将对这些化合物在小鼠AKI模型中的疗效进行测试。