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

基本信息

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
项目类别：
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

项目摘要

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.