Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
基本信息
- 批准号:10281742
- 负责人:
- 金额:$ 70.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccidentsAcetylcholinesteraseAdvanced DevelopmentAffinityAnimalsAntidotesAtropineAttenuatedBehaviorBinding ProteinsBlood - brain barrier anatomyBrainCaviaChemicalsChemistryCholinesterase InhibitorsClinical ChemistryConsultationsConvulsionsDataDevelopmentDoseDrug InteractionsDrug KineticsEvaluationExposure toFutureGTP-Binding Protein alpha Subunits, GsGoalsHematologyHepaticHumanIn VitroIntellectual PropertyLaboratoriesLaboratory AnimalsLeadLegal patentLicensureLifeMetabolismMethodsMicrosomesMiniature SwineMuscarinic Acetylcholine ReceptorNo-Observed-Adverse-Effect LevelOrganophosphatesOximesPathologicPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePharmacologyPharmacology and ToxicologyPlasmaPlasma ProteinsPoisoningPropertyProperty RightsRattusRecurrenceResearchSafetySarinSavingsSeizuresSeriesSolubilitySolventsSpecific qualifier valueTestingTherapeuticToxic effectTremoractive methodattenuationbasecommercializationdosageefficacy testingexperimental studygenotoxicityimprovedin vivolead optimizationlipophilicitymalemanufacturing scale-upmass casualtymeetingsmethylphosphonatenerve agentneuropathologyneuroprotectionnovelorganophosphate poisoningpreservationrespiratoryresponsescale upsex
项目摘要
7. Project Summary/Abstract
Many of the organophosphate (OP) anticholinesterases, such as nerve agents, are highly toxic. Terrorist
actions or accidents involving OPs could lead to mass casualties with potentially high levels of lethality. The
current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the
inhibited acetylcholinesterase (2-PAM in the US). However, 2-PAM is not always effective at saving lives and
cannot effectively penetrate the blood brain barrier, so 2-PAM can leave victims poorly protected. An improved
oxime therapeutic is needed to counteract nerve agent lethality and assist with neuroprotection, so that both
life and brain function may be preserved. Our laboratories have invented, patented and licensed a platform of
substituted phenoxyalkyl pyridinium oximes that have shown better survival efficacy than 2-PAM and, unlike 2-
PAM, attenuation of signs of seizure-like behavior and neuropathology in rats exposed to high levels of highly
relevant nerve agent surrogates. Limited studies in male guinea pigs against sarin have also shown efficacy.
With our current CounterACT Lead Identification U01 the efficacious compounds (the “actives”) have been
down-selected to a lead and an alternate, with Oxime 20 being proposed as the Active Pharmaceutical
Ingredient (API). The proposed project will build on the present survival efficacy, pharmacokinetic and API
toxicity information in rats. Initially a superior vehicle for the API will be developed as a better solvent for the
lipophilic API. A pharmacodynamic aim (Aim 1) will determine in rats (both sexes) whether a lower dosage of
the API will be effective in promoting survival of lethal dosages of a sarin surrogate (nitrophenyl isopropyl
methylphosphonate, NIMP; a G agent chemistry) and a VX surrogate (nitrophenyl ethyl methylphosphonate,
NEMP; a V agent chemistry) alone or in combination with 2-PAM. A pharmacokinetic (PK) aim (Aim 2) will
determine the PK of the API in the new vehicle, plasma protein binding and hepatic microsomal metabolism in
rats of both sexes and will introduce studies of a larger non-rodent test species, the Gottingen minipig, both
sexes. An oxime toxicity aim (Aim 3) will investigate dose responses of the API for gross pathological,
histopathological, clinical chemistry and hematology adverse results in rats and minipigs of both sexes to
identify a Maximum Tolerated Dosage and a No Observed Adverse Effect Level, as well as in vitro genotoxicity
and drug-drug interactions for CYPs and transporters. A chemistry aim (Aim 4) will support the previous 3 aims
by providing the synthesis of NIMP, NEMP and the API, produce a new vehicle with improved solvent
properties, evaluate API stability, and provide initial plans for manufacturing and Chemical Manufacturing
Controls. All studies will be non-GLP and will follow FDA guidance from pre-IND meetings. The overarching
goal of this Lead Optimization project is to provide optimized pharmacological and toxicological information on
our lead oxime in both sexes of two species that will prepare the API to move into advanced development
toward FDA approval.
7.项目总结/摘要
许多有机磷(OP)抗胆碱酯酶,如神经毒剂,是高毒性的。恐怖
涉及行动方案的行动或事故可能导致大规模伤亡,并具有潜在的高度致命性。的
目前的治疗包括毒蕈碱受体拮抗剂阿托品和一种肟再活化剂,
抑制乙酰胆碱酯酶(2-PAM在美国)。然而,2-PAM并不总是有效地挽救生命,
不能有效地穿透血脑屏障,因此2-PAM可能会使受害者得不到很好的保护。一种改进
需要肟治疗剂来抵消神经毒剂的致命性并协助神经保护,以便两者都
生命和大脑功能可以被保留。我们的实验室已经发明了一个平台,并获得了专利和许可,
取代的苯氧基烷基吡啶肟已经显示出比2-PAM更好的存活功效,并且与2-PAM不同,
PAM,在暴露于高水平高浓度的
相关的神经毒剂替代品在雄性豚鼠身上进行的对抗沙林毒气的有限研究也显示出有效性。
通过我们目前的CounterACT电极导线识别U 01,有效化合物(“活性物质”)已被
向下选择为先导药物和替代药物,拟定将肟20作为活性药物
成分(API)。拟定项目将建立在现有生存疗效、药代动力学和API的基础上
大鼠的毒性信息。最初,将开发API的上级载体作为更好的溶剂,
亲脂性API。药效学目的(目的1)将确定大鼠(两种性别)中较低剂量的
该API将有效促进致死剂量沙林替代物(硝基苯异丙基)的存活
甲基膦酸酯,NIMP; G试剂化学)和VX替代物(甲基膦酸硝基苯基乙酯,
NEMP; V试剂化学)单独或与2-PAM组合。药代动力学(PK)目标(目标2)将
测定新溶媒中API的PK、血浆蛋白结合率和肝微粒体代谢
将引入一个更大的非啮齿类动物试验物种的研究,哥廷根小型猪,
性别肟毒性目的(目的3)将研究API的剂量反应,
两种性别大鼠和小型猪的组织病理学、临床化学和血液学不良结果,
确定最大耐受剂量和无明显不良作用水平,以及体外遗传毒性
以及CYP和转运蛋白的药物间相互作用。化学目标(目标4)将支持前3个目标
通过提供NIMP、NEMP和API的合成,生产具有改进的溶剂的新载体
性质,评价API稳定性,并为生产和化学品生产提供初步计划
对照所有研究均为非GLP研究,并将遵循IND前会议的FDA指南。总体
本电极导线优化项目的目标是提供以下方面的优化药理学和毒理学信息
我们的铅肟在两种性别的物种,将准备API进入先进的发展
FDA的批准。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Janice Elaine Chambers其他文献
Janice Elaine Chambers的其他文献
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{{ truncateString('Janice Elaine Chambers', 18)}}的其他基金
Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
- 批准号:
10660985 - 财政年份:2021
- 资助金额:
$ 70.69万 - 项目类别:
Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
- 批准号:
10459573 - 财政年份:2021
- 资助金额:
$ 70.69万 - 项目类别:
Identification of Novel Brain-penetrating Phenoxyalkyl Pyridinium Oxime Countermeasures
新型脑穿透性苯氧基烷基吡啶肟对策的鉴定
- 批准号:
9928535 - 财政年份:2018
- 资助金额:
$ 70.69万 - 项目类别:
Identification of novel brain-penetrating oxime antidotes for phorate toxicity
新型脑穿透性肟解毒剂甲拌磷毒性的鉴定
- 批准号:
9633107 - 财政年份:2018
- 资助金额:
$ 70.69万 - 项目类别:
Identification of novel brain-penetrating oxime antidotes for phorate toxicity
新型脑穿透性肟解毒剂甲拌磷毒性的鉴定
- 批准号:
9788116 - 财政年份:2018
- 资助金额:
$ 70.69万 - 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
- 批准号:
8544717 - 财政年份:2014
- 资助金额:
$ 70.69万 - 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
- 批准号:
9331890 - 财政年份:2014
- 资助金额:
$ 70.69万 - 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
- 批准号:
9091668 - 财政年份:2014
- 资助金额:
$ 70.69万 - 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
- 批准号:
8846691 - 财政年份:2014
- 资助金额:
$ 70.69万 - 项目类别:
Relationship of Blood Esterases, Pesticide Exposure and Cardiovascular Disease
血酯酶、农药暴露与心血管疾病的关系
- 批准号:
7906342 - 财政年份:2009
- 资助金额:
$ 70.69万 - 项目类别:
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