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

• 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
• 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

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.

项目摘要 这个以本科生为中心的项目的目的是开发化学合成的创新， 产生新型的热铅化合物，用于刺激性使用障碍。 刺激性使用障碍会影响数百万美国人。涉及兴奋剂的过量死亡增加了 近年来，他们在19009年的大流行期间猛增，特别是 OOPIEAD滥用。没有FDA批准的用于刺激使用障碍的药物，但是蛋白质酪氨酸 磷酸酶受体型D（PTPRD）已被确定为重要的治疗靶点。遗传 研究将较高的PTPRD表达水平与对药物滥用和成瘾的倾向更大，以及 减少PTPRD活动可减少小鼠的可卡因寻求行为。因此，PTPRD抑制剂提供了潜力 开发用于兴奋剂障碍的治疗方法的新途径。 天然产物非甲酸是一种潜在的PTPRD抑制剂。化学合成急性酸已经 极度困难，因此简化的模拟类似于7-BIA，作为靶向铅化合物出现 ptprd。 7-BIA在综合上比不藻酸更容易获得，但潜力较小。脂酸（和 7-BIA）被张贴以在PTPRD催化域中可逆地绑定，揭开反应性释醛和 然后将其共同连接到关键的半胱氨酸居住区，不可逆转地阻止PTPRD活动。 提出了不酸性酸类似物的合成。初步结果建立了收敛的5步合成 （最长的线性序列，lls）的非甲酸酸，而先前的方法需要16-20个线性步骤。 这里的关键步骤是一个[4+2]苯式，以组装完全取代的Arene Core和Carbon框架。 本科生将开发合成和晚期的方法和相关方法 非甲酸类似物的功能化，称为“肺病”。 PTPRD将评估化合物 抑制活性和选择性，以及甲酸酸和7-BIA作为阳性对照。理由 工作是基于甲酸酸的PTPRD抑制剂可以导致刺激使用障碍的药物疗法。 三个完成者的目的重点是：（1）开发illudalogs的合成化学，包括晚期 舞台功能化和新的二苯； （2）建造和维护合成复合库 用于结构活性关系（SAR）研究和铅鉴定的各种疾病； （3）创建 PTPRD酶学和细胞生物学的功能问题。预期的结果包括创新 化学合成可为PTPRD抑制剂和问题提供变革性访问。这些结果 将支持PTPRD的治疗潜力的发展作为抗假药药物的靶标。

项目成果

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.