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.

项目总结-探针和药物优化核心（PPOC）-核心B 加州大学戴维斯分校反ACT卓越中心的总体目标是识别和推进改进 用于停止癫痫发作和预防急性癫痫引起的长期后果的医疗对策 化学威胁剂中毒，特别是有机磷酸胆碱酯酶抑制剂， 二异丙基氟磷酸盐（DFP）、对氧磷和梭曼，或GABAA受体阻断剂，如四亚甲基- 二磺毒鼠强（TETS）、印防己毒素和荷包牡丹碱。 核心B（探针和药物优化核心）的作用是通过以下方式促进中心的总体目标 提供一般药物化学、配方和药理学支持。核心B将作为一个整体 通过支持项目1、2和3，并与核心A、分析和评价中心密切合作， 化学核心核心B将合成化学威胁剂四亚甲基二磺基四胺（TETS）， 具体机制探针的个别项目，包括TETS-半抗原和类似物的发展， a核心A中的TETS检测试验。核心B将进一步利用其药物化学专业知识， 表征潜在的新型疗法，包括可溶性环氧化物水解酶（sEH）抑制剂、双重 sEH/环加氧酶-2（考克斯-2）或sEH/磷酸二酯酶抑制剂，小电导钙激活剂， 激活钾通道（KCa 2），小胶质细胞电压门控钾通道Kv1.3的阻断剂，以及 AMPA、ryanodine或GABA受体拮抗剂，根据项目要求。具有专用于探测和 试剂设计、合成和/或验证将有助于确保整个 加州大学戴维斯分校中心和反ACT计划的项目。与第一个项目期相比， 重点是提供用于体外筛选的不同化合物的文库，现在的重点将是 优化先前确定的先导化合物和候选治疗剂的生物利用度、半衰期和中枢神经毒性， 系统（CNS）渗透。核心B将进一步投入大量精力，以实现快速有效性和安全性 筛选候选治疗剂和治疗组合，以帮助告知化合物组合和剂量， 选择项目2和项目3。