Probe and Pharmaceutical Optimization Core (PPOC)

项目摘要-探测器和药物优化核心(PPOC)-核心B 加州大学戴维斯分校卓越对抗中心的总体目标是确定和推进改进 阻止癫痫发作和预防急性发作的长期后果的医学对策 中毒于化学威胁物质，特别是有机磷胆碱酯酶抑制剂，如 二异丙基氟磷酸盐(DFP)，对氧磷和梭曼，或GABAA受体阻滞剂，如四亚甲基- 毒鼠强、印防己毒素和荷包牡丹碱。 核心B是探测器和药物优化核心，其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、制剂和药理方面的支持。核心B将作为一个整体发挥作用 通过支持项目1、2和3，并通过与核心A、分析中心 化学核心。核心B将合成化学威胁剂四亚甲基二磺酸毒鼠强(TETS)和 针对单个项目的特定机制探测，包括用于开发TETS半抗原和类似物的 核心A的TETS检测分析B核心将进一步利用其药物化学专业知识合成和 表征潜在的新疗法，包括可溶性环氧化物水解酶(SEH)抑制剂，Dual SeH/环氧合酶-2(COX-2)或sEH/磷酸二酯酶抑制剂，小电导钙激活剂- 激活的钾通道(KCa2)，小胶质细胞电压门控性钾通道Kv1.3的阻断剂，以及 项目所需的AMPA、ryanodine或GABA受体拮抗剂。具有专门用于探测和控制的核心 试剂的设计、合成和/或验证将有助于确保 加州大学戴维斯分校的项目和对抗计划。与第一个项目期形成对比，在第一个项目期 重点是提供用于体外筛选的各种化合物的文库，现在的重点将是 为生物利用度、半衰期和中枢神经系统优化先前确定的先导药物和候选治疗药物 系统(CNS)渗透。核心B将进一步投入大量努力，实现快速有效和安全 筛选候选疗法和治疗组合，以帮助了解化合物组合和剂量- 项目2和项目3的选择。

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.