Optimization of microtubule-stabilizing triazolopyrimidines as therapeutics for Alzheimer's disease and related tauopathies

优化微管稳定三唑并嘧啶作为阿尔茨海默病和相关 tau蛋白病的治疗方法

• 批准号: 10553899
• 负责人: KURT R. BRUNDEN
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553899
• 关键词: Acute; Adverse effects; Alzheimer' s disease therapeutic; Biological Assay; Dose; Drug Kinetics; Intravenous; Laboratories; Maximum Tolerated Dose; Microtubule Stabilization; Neurons; Oral; Pharmacodynamics; Prodrugs; Tauopathies; Testing; Wild Type Mouse; Work

Statement of Work Specific activities overseen by the Brunden laboratory include: 1) testing of prodrugs in established HEK293 and neuron microtubule stabilization assays; 2) intravenous and oral pharmacokinetic testing of prodrugs to determine the rate of conversion of prodrugs to the desired active compound; 3) assessment of preferred prodrugs for pharmacodynamic effect in wild-type mice to establish the minimum effective dose and duration of compound effect; and 4) determination of preferred prodrug acute maximum tolerated dose and the no adverse effect dose after 3 weeks of dosing.

工作说明书 布伦登实验室监督的具体活动包括：1)在已建立的 HEK293和神经元微管稳定化试验；2)静脉和口服药代动力学试验 前药物，以确定前药物向所需活性化合物的转化率；3)评估 优选前体药物在野生型小鼠体内的药效学最低效价的确定 复合作用的剂量和持续时间；4)首选前体药物急性最大限度的测定 给药3周后的耐受量和无不良反应剂量。

项目成果

Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights.

• DOI: 10.1021/acs.jmedchem.2c01411
• 发表时间: 2023-01-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Alle, Thibault;Varricchio, Carmine;Yao, Yuemang;Lucero, Bobby;Nzou, Goodwell;Demuro, Stefania;Muench, Megan;Vuong, Khoa D.;Oukoloff, Killian;Cornec, Anne-Sophie;Francisco, Karol R.;Caffrey, Conor R.;Lee, Virginia M. -Y.;Smith III, Amos B.;Brancale, Andrea;Brunden, Kurt R.;Ballatore, Carlo
• 通讯作者: Ballatore, Carlo