Probe and Pharmaceutical Optimization Core (PPOC)

探针和药物优化核心 (PPOC)

• 批准号: 10204121
• 负责人: HEIKE WULFF
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204121
• 关键词: AMPA Receptors; Acute; Allopregnanolone; Analytical Chemistry; Anticonvulsants; Bicuculline; Biological Availability; Chemicals; Chemistry; Cholinesterase Inhibitors; Data; Development; Dose; Drug Kinetics; Ensure; Epoxide hydrolase; Formulation; GABA Antagonists; Goals; Half-Life; Haptens; In Vitro; Individual; Intoxication; Isoflurophate; Libraries; Minocycline; Molecular Target; Neuraxis; Organophosphates; PTGS2 gene; Paraoxon; Penetration; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Phosphodiesterase Inhibitors; Picrotoxin; Property; Reagent; Reproducibility; Riluzole; Role; Ryanodine Receptor Calcium Release Channel; Safety; Seizures; Soman; Therapeutic; Voltage-Gated Potassium Channel; Work; analog; calcium-activated potassium channel small-conductance; chemical threat; cyclooxygenase 2; design; detection assay; efficacy testing; improved; in vivo; inhibitor/antagonist; medical countermeasure; novel; novel therapeutics; prevent; programs; receptor; safety study; screening; stability testing; tetramethylenedisulfotetramine; therapeutic candidate

Project Summary – Probe and Pharmaceutical Optimization Core (PPOC) – Core B The overall goal of the UC Davis CounterACT Center of Excellence is to identify and advance improved medical countermeasures for stopping seizures and preventing long-term consequences resulting from acute intoxication with chemical threat agents, specifically organophosphate cholinesterase inhibitors like diisopropylfluorophosphate (DFP), paraoxon and soman, or GABAA receptor blockers like tetramethylene- disulfotetramine (TETS), picrotoxin and bicuculline. The role of Core B, the Probe and Pharmaceutical Optimization Core, is to promote the overall Center goal by providing general medicinal chemistry, formulation and pharmacology support. Core B will function as an integral component of the Center by supporting Projects 1, 2 and 3, and by closely collaborating with Core A, the Analytical Chemistry Core. Core B will synthesize the chemical threat agent tetramethylenedisulfotetramine (TETS) and specific mechanistic probes for the individual projects, including TETS-haptens and analogs for the development of a TETS detection assay in Core A. Core B will further use its medicinal chemistry expertise to synthesize and characterize potential novel therapeutics, including soluble epoxide hydrolase (sEH) inhibitors, dual sEH/cyclooxygenase-2 (COX-2) or sEH/phosphodiesterase inhibitors, activators of small-conductance calcium- activated potassium channels (KCa2), blockers of the microglial voltage-gated potassium channel Kv1.3, as well as AMPA, ryanodine or GABA receptor antagonists, as required by the projects. Having a core dedicated to probe and reagent design, synthesis and/or verification will help ensure consistency, efficacy and reproducibility across the projects of the UC Davis Center and the CounterACT program. In contrast to the first project period, where the emphasis was on delivering libraries of diverse compounds for in vitro screening, the emphasis now will be on optimizing previously identified leads and candidate therapeutics for bioavailability, half-life and central nervous system (CNS) penetration. Core B will further devote significant effort to performing rapid efficacy and safety screens of candidate therapeutics and therapeutic combinations to help inform compound-combinations and dose- selection for Projects 2 and 3.

项目摘要 - 探测和药物优化核心（PPOC） - 核心B 加州大学戴维斯分校抵抗卓越中心的总体目标是识别和提高改进 医疗对策，以阻止癫痫发作和防止急性导致长期后果 化学威胁剂中毒，特别是有机磷酸盐胆碱酯酶抑制剂 二异丙氟磷酸二异丙磷酸（DFP），paraoxon和Soman，或Gabaa受体阻滞剂，例如四甲基 - 二硫胺（TET），Picrototoxin和bicuculline。 核心B的作用，探针和药物优化核心是通过通过 提供一般的医学化学，配方和药理学支持。核心B将充当不可或缺的 通过支持项目1、2和3的组成部分，并通过与核心A的密切合作，分析 化学核心。核B将合成化学威胁剂四甲基二硫胺（TET）和 各个项目的特定机械项目，包括TET-Haptens和类似物的开发 核心A中的TET检测测定法将进一步使用其医学化学专家合成和 表征潜在的新型疗法，包括固体环氧水解酶（SEH）抑制剂，双重 SEH/环氧合酶-2（COX-2）或SEH/磷酸二酯酶抑制剂，小传导钙的活化剂 活化的钾通道（KCA2），小胶质电压门控钾通道KV1.3的阻滞剂以及 根据项目的要求，AMPA，Ryanodine或GABA受体拮抗剂。拥有致力于探测和的核心 试剂设计，合成和/或验证将有助于确保整个整个的一致性，效率和可重复性 加州大学戴维斯分校中心的项目和抵消计划。与第一个项目时期相比 重点是提供体外筛查的各种化合物的库，现在将重点 优化先前确定的铅和候选疗法，以实现生物利用度，半衰期和中枢神经 系统（CNS）穿透。核心B将进一步降低巨大的努力以执行快速效率和安全性 候选治疗和治疗组合的筛选，以帮助提供化合物组合和剂量 - 选择项目2和3。