Chemical synthesis of illudalic acid analogs for stimulant use disorder

用于兴奋剂使用障碍的乌尔达酸类似物的化学合成

基本信息

批准号：
10514808
负责人：
GREGORY B DUDLEY
金额：
$ 38万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514808
关键词：
Acidity Acids Affect Aldehydes American Anhydrides Animal Model Automobile Driving Behavior Benzene Binding Biotin COVID-19 pandemic Carbon Carboxylic Acids Catalytic Domain Cells Cellular biology Chemistry Cocaine Cysteine Development Enzymatic Biochemistry FDA approved Future Genetic study Goals Hydrogen Bonding In Vitro Label Lactones Lead Libraries Link Masks Methodology Mus Naphthalene Naphthalenes Natural Products Outcome Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Phosphoric Monoester Hydrolases Play Protein Tyrosine Phosphatase Publishing Pyrones Research Personnel Role Route Solubility Stimulant Structure Structure-Activity Relationship Substance Addiction Substance abuse problem Synthesis Chemistry Testing Therapeutic Variant Work addiction analog base chemical synthesis cocaine self-administration conditioned place preference design drug development drug discovery experimental study functional group in vitro activity in vivo inhibitor innovation novel novel strategies novel therapeutics opioid abuse overdose death pharmacophore receptor scaffold screening stimulant use disorder synaptogenesis targeted treatment tetralin therapeutic development therapeutic lead compound therapeutic target undergraduate research experience undergraduate student

项目摘要

PROJECT SUMMARY The objective of this undergraduate-centered project is to develop innovations in chemical synthesis that produce novel therapeutic lead compounds for stimulant use disorder. Stimulant use disorder affects millions of Americans. Overdose deaths involving stimulants have increased significantly in recent years, and they surged during the COVID-19 pandemic, especially in conjunction with opioid abuse. There are no FDA-approved medications for stimulant use disorder, but the protein tyrosine phosphatase receptor-type D (PTPRD) has been identified as an important therapeutic target. Genetic studies link higher PTPRD expression levels with greater propensity for substance abuse and addiction, and reducing PTPRD activity reduces cocaine-seeking behavior in mice. PTPRD inhibitors thus provide potential new avenues for developing treatments for stimulant use disorder. The natural product illudalic acid is a potent PTPRD inhibitor. Chemical synthesis of illudalic acid has been prohibitively difficult, so a simplified analog known as 7-BIA emerged as a lead compound for targeting PTPRD. 7-BIA was more synthetically accessible than illudalic acid but is less potent. Illudalic acid (and 7-BIA) is postulated to bind reversibly in the PTPRD catalytic domain, unmask a reactive dialdehyde, and then ligate covalently to a key cysteine residue, irreversibly blocking PTPRD activity. Synthesis of illudalic acid analogs is proposed. Preliminary results establish a convergent 5-step synthesis (longest linear sequence, LLS) of illudalic acid, whereas prior approaches require 16-20 linear steps. The key step here is a [4+2] benzannulation to assemble the fully substituted arene core and carbon framework. Undergraduate students will develop the approach and related methodology for the synthesis and late-stage functionalization of illudalic acid analogs, called “illudalogs”. Compounds will be evaluated for PTPRD inhibitory activity and selectivity, alongside illudalic acid and 7-BIA as positive controls. The rationale for this work is that illudalic acid-based PTPRD inhibitors can lead to pharmacotherapies for stimulant use disorder. Three complementary aims focus on: (1) developing the synthetic chemistry of the illudalogs, including late- stage functionalization and a new benzannulation; (2) building and maintaining a synthetic compound library of diverse illudalogs for structure-activity relationship (SAR) studies and lead identification; and (3) creating functional probes for PTPRD enzymology and cell biology. Expected outcomes include innovations in chemical synthesis that provide transformative access to PTPRD inhibitors and probes. These outcomes will support development of the therapeutic potential of PTPRD as a target for antiaddiction medication.

项目概要这个以本科生为中心的项目的目标是开发化学合成创新，生产用于兴奋剂使用障碍的新型治疗先导化合物。兴奋剂使用障碍影响了数百万美国人，因服用兴奋剂而导致的过量死亡有所增加。近年来显着增加，并且在 COVID-19 大流行期间激增，尤其是在阿片类药物滥用目前还没有 FDA 批准的治疗兴奋剂使用障碍的药物，但蛋白质酪氨酸。 D 型磷酸酶受体 (PTPRD) 已被确定为重要的遗传治疗靶点。研究将更高的 PTPRD 表达水平与更大的药物滥用和成瘾倾向联系起来，并且降低 PTPRD 活性可减少小鼠的可卡因寻求行为，从而提供了潜在的可能性。开发兴奋剂使用障碍治疗方法的新途径。天然产物异丁烯酸是一种有效的 PTPRD 抑制剂。异丁烯酸已被化学合成。极其困难，因此一种称为 7-BIA 的简化类似物出现作为靶向的先导化合物 PTPRD。7-BIA 比伊豆酸更容易合成，但效力较差。 7-BIA) 被假定可逆地结合在 PTPRD 催化结构域中，揭示活性二醛，并且然后与关键的半胱氨酸残基共价连接，不可逆地阻断 PTPRD 活性。初步结果表明，乌杜达酸类似物的合成采用了收敛的 5 步合成法。（最长线性序列，LLS），而之前的方法需要 16-20 个线性步骤。这里的关键步骤是 [4+2] 苯并环化来组装完全取代的芳烃核心和碳框架。本科生将开发综合和后期阶段的方法和相关方法被称为“illudalogs”的illudalic酸类似物的功能化将针对PTPRD进行评估。抑制活性和选择性，以及乌贼酸和 7-BIA 作为阳性对照。工作的重点是基于乌鲁达酸的 PTPRD 抑制剂可以导致兴奋剂使用障碍的药物疗法。三个互补的目标集中在：（1）开发 illusdalog 的合成化学，包括晚期- (2) 合成化合物库的构建和维护用于结构-活性关系（SAR）研究和先导化合物识别的各种幻觉；（3）创建 PTPRD 酶学和细胞生物学的功能探针的预期成果包括创新。化学合成提供了 PTPRD 抑制剂和探针的革命性途径。将支持开发 PTPRD 作为抗成瘾药物靶标的治疗潜力。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1

真菌天然产物伊杜达酸的衍生物抑制蛋白组氨酸磷酸酶PHPT1的活性

DOI：
10.1002/cmdc.202300187
发表时间：
2023
期刊：
ChemMedChem
影响因子：
3.4
作者：
Wang, Hanfei;Gaston, Jr., Robert;Ahmed, Kh Tanvir;Dudley, Gregory B.;Barrios, Amy M.
通讯作者：
Barrios, Amy M.