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 – 探针和药物优化核心 (PPOC) – 核心 B 加州大学戴维斯分校 CounterACT 卓越中心的总体目标是确定并推进改进的 停止癫痫发作并预防急性发作造成的长期后果的医疗对策 化学威胁剂中毒，特别是有机磷酸酯胆碱酯酶抑制剂，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- 二磺四胺（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、制剂和药理学支持，核心 B 将作为一个整体发挥作用。 通过支持项目 1、2 和 3，并与核心 A（分析中心）密切合作，成为该中心的组成部分 化学核心。核心 B 将合成化学威胁剂四亚甲基二磺四胺 (TETS) 和 各个项目的具体机制探针，包括 TETS 半抗原和类似物，用于开发 核心 A 中的 TETS 检测分析。核心 B 将进一步利用其药物化学专业知识来合成和 表征潜在的治疗小说，包括可溶性环氧化物水解酶（sEH）抑制剂、双重 sEH/环氧合酶-2 (COX-2) 或 sEH/磷酸二酯酶抑制剂、小电导钙激活剂 激活的钾通道 (KCa2)、小胶质细胞电压门控钾通道 Kv1.3 的阻滞剂，以及 AMPA、ryanodine 或 GABA 受体拮抗剂，根据项目要求有一个专门用于探测和检测的核心。 试剂设计、合成和/或验证将有助于确保整个过程的一致性、有效性和可重复性 加州大学戴维斯分校中心和 CounterACT 项目的项目 与第一个项目时期相比， 重点是提供用于体外筛选的多种化合物库，现在的重点是 优化先前确定的先导化合物和候选疗法的生物利用度、半衰期和中枢神经系统 Core B 将进一步致力于实现快速功效和安全性。 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 3 的选择。