Optimization of novel thioesters as a therapeutic strategy for combating opioid overdoses and abuse

优化新型硫酯作为对抗阿片类药物过量和滥用的治疗策略

基本信息

批准号：
10015761
负责人：
stephen john lewis
金额：
$ 49.41万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015761
关键词：
ARRB1 gene Address Binding Blood Blood gas Cause of Death Cell Membrane Permeability Chemical Structure Chemicals Chemistry Clinical Trials Cysteine Data Deuterium Diazepam Drug Kinetics Esters Female Fentanyl Future Human Hydrogen In Vitro Injections Intellectual Property Intramuscular Intravenous Intravenous Bolus Lead Letters Life Liquid substance Mass Spectrum Analysis Mechanics Methamphetamine Methods Molecular Molecular Conformation Morphine Naloxone Naltrexone Opioid Opioid Antagonist Parents Patients Pharmacodynamics Pharmacology Property Rights Public Health Rattus Resistance Rest Route SKIL gene Safety Series Site Structure Sufentanil Techniques Technology Transfer Testing Therapeutic Therapeutic Agents Time Tissues Ventilatory Depression Withdrawal Withdrawal Symptom Work analog arrestin 1 arrestin 2 carfentanil chemical stability combat commercialization design drug development in silico in vivo male mecysteine molecular dynamics mu opioid receptors novel novel therapeutics opioid abuse opioid epidemic opioid overdose synthetic opioid thioester

ARRB1 gene Address Binding Blood Blood gas Cause of Death Cell Membrane Permeability Chemical Structure Chemicals Chemistry Clinical Trials Cysteine Data Deuterium Diazepam Drug Kinetics Esters Female Fentanyl Future Human Hydrogen In Vitro Injections Intellectual Property Intramuscular Intravenous Intravenous Bolus Lead Letters Life Liquid substance Mass Spectrum Analysis Mechanics Methamphetamine Methods Molecular Molecular Conformation Morphine Naloxone Naltrexone Opioid Opioid Antagonist Parents Patients Pharmacodynamics Pharmacology Property Rights Public Health Rattus Resistance Rest Route SKIL gene Safety Series Site Structure Sufentanil Techniques Technology Transfer Testing Therapeutic Therapeutic Agents Time Tissues Ventilatory Depression Withdrawal Withdrawal Symptom Work analog arrestin 1 arrestin 2 carfentanil chemical stability combat commercialization design drug development in silico in vivo male mecysteine molecular dynamics mu opioid receptors novel novel therapeutics opioid abuse opioid epidemic opioid overdose synthetic opioid thioester

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项目摘要

Abstract The current opioid crisis in the US is fueled by the availability and extreme potency of the synthetic opioids fentanyl, carfentanil and sufentanil. The major objective of this U-01 proposal is to optimize our lead thiolester candidate, D-cysteine ethyl ester (JMS-19) as a viable therapeutic agent to elicit a rapid and sustained reversal of opioid-induced respiratory depression (OIRD, a major cause of death) elicited by the potent synthetic opioids fentanyl, sufentanil and carfentanil, without eliciting withdrawal symptoms in opioid-addicted subjects. This work will involve a series of in silico, in vitro, ex vivo, and in vivo techniques that will first optimize the chemical structure of JMS-19 (i.e., produce a derivative with greater efficacy and chemical stability) and then determine the pharmacodynamics, pharmacokinetics, and safety for the lead compound, laying the groundwork for seeking FDA approval for studies in humans. An example flow of drug development will be D-CYSee to D- cysteine methyl ester (that we predict will be approximately 100 times more potent than D-CYSee) to S-nitroso (SNO)-D-cysteine methyl ester (we have established that SNO-D-cysteine ethyl ester is approximately 1,000 times more potent than D-CYSee) to S-ethyl-D-cysteine methyl ester and S-sulfinic-D-cysteine methyl ester (which we predict will be equally potent to the SNO-derivatives but much more chemically stable and resistant to enzymatic degradation). We will provide compelling evidence that JMS-19 reverses OIRD without eliciting any withdrawal symptoms in rats treated with morphine or fentanyl, and will provide key data, which strongly suggest that the primary mechanism of action for JMS-19 and the related thiolesters is by binding to and inactivating β-arrestins 1 and 2. These molecular key targets will allow us to optimize JMS-19 for maximum efficacy in silico and in vitro, for ultimate testing against the opioids in freely-moving male and female rats. This will combine molecular dynamics simulations which will optimize JMS-19's membrane permeability and binding to active β-arrestins 1 and 2. These computational results will be confirmed experimentally by means of hydrogen deuterium exchange mass spectrometry before the final pharmacodynamics data will be shared with the rest of the project. The in vivo studies will involve (1) testing D-CYSee and optimized structural analogues against fentanyl, carfentanil and sufentanil to determine in detail how out test thiolesters reverse the negative effects of the opioid on ventilatory timing and mechanics and arterial blood-gas chemistry in freely-moving male and female rats, and (2) combinations of fentanyl and methamphetamine, and often deadly (ventilatory- depressant) combination in humans. Finally, we will perform pharmacokinetic studies on at least one of the optimized D-CYSee derivatives to establish the temporal distribution of these compounds in the absence and presence of fentanyl in order to relate the efficacy of the thiolesters with the pharmacological reversal of OIRD. In summary, we are confident that our project will produce a series of active thiolesters with potent abilities to elicit rapid and sustained reversal of the OIRD elicited by potent synthetic opioids.

抽象的当前美国的阿片类药物危机受到合成阿片类药物的可用性和极大效力的助长芬太尼，carfentanil和sufentanil。该U-01提案的主要目的是优化我们候选者D-结晶乙基酯（JMS-19）作为可行的治疗剂，以引起快速而持续的逆转潜在的合成阿片类药物引起的阿片类药物诱导的呼吸抑郁症（OIRD，主要原因）芬太尼，苏芬太尼和carfentanil，没有引起阿片类药物成瘾受试者的戒断症状。这工作将涉及一系列的硅，体外，离体和体内技术，这些技术将首先优化化学物质 JMS-19的结构（即产生具有更高效率和化学稳定性的导数），然后确定铅化合物的药效学，药代动力学和安全性，为寻求FDA批准人类研究。药物开发的一个例子将是d-cysee到d- 半硝基的半胱氨酸甲酯（我们预测，这将是比d-cysee的100倍）（SNO）-D-固结甲基酯（我们已经确定SNO-D-半胱氨酸乙酯约为1,000 比d-cysee）对S-乙基-D-半胱氨酸甲酯和S-硫酸-D-甲基甲酯的潜力更大（我们预测，这对于SNO衍生品将同样潜在，但更稳定和抗性酶促降解）。我们将提供令人信服的证据，表明JMS-19不引起逆转而逆转用吗啡或芬太尼治疗的大鼠的任何戒断症状表明JMS-19和相关硫代菌的主要作用机理是通过与和灭活β-arrestins 1和2。这些分子关键目标将使我们能够优化JMS-19以最大在硅和体外的功效，以对自由移动的雄性和雌性大鼠的阿片类药物进行最终测试。这将结合分子动力学模拟，以优化JMS-19的膜渗透性和结合对于活动的β-art蛋白1和2。这些计算结果将通过实验确认在最终药效学数据之前将与氢氘交换质谱项目的其余部分。体内研究将涉及（1）测试d-cysee和优化的结构类似物反对芬太尼，carfentanil和sufentanil，以详细确定测试硫醇如何逆转阴性阿片类药物对自由移动的通风时间和力学和动脉血液化学的影响雄性和雌性大鼠，以及（2）芬太尼和甲基苯丙胺的组合，以及通常致命的（通风 - 人类的抑郁剂）组合。最后，我们将对至少一项进行药代动力学研究优化的D-CySEE衍生物在不存在的情况下建立这些化合物的临时分布芬太尼的存在是为了将硫醇的效率与Oird的药物逆转联系起来。总而言之，我们相信我们的项目将产生一系列具有潜在能力的活性硫醇引起潜在的合成阿片类药物引起的oird的快速和持续逆转。