PTPRD phosphatase inhibitors for stimulant use disorders

PTPRD 磷酸酶抑制剂治疗兴奋剂使用障碍

• 批准号: 10653070
• 负责人: George Richard Uhl
• 金额: $ 139.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653070
• 关键词: Abstinence; Acute; Address; Admission activity; Advanced Development; American; Amphetamines; Attention deficit hyperactivity disorder; Biological Availability; Brain; Cocaine; Data; Development; Disease; Dose; Dose Limiting; FDA approved; Formulation; Good Manufacturing Process; Human; Ileus; In Vitro; Individual; Intellectual Property; Knock-out; Ligands; Metabolic; Monitor; Mus; Narcolepsy; National Institute of Drug Abuse; Oral; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebos; Prevention; Property; Protein Tyrosine Phosphatase; Rattus; Reporting; Research; Rewards; Rodent; Role; Stimulant; Testing; Therapeutic Index; Toxic effect; Variant; Wild Type Mouse; Work; Writing; addiction; base; carcinogenicity; cocaine use; conditioned place preference; drug action; drug reward; first-in-human; genetic variant; in vivo; methamphetamine use; mouse model; novel; novel therapeutics; overdose death; pharmacokinetics and pharmacodynamics; pharmacologic; phase 1 testing; phosphatase inhibitor; receptor; small molecule; stimulant use; stimulant use disorder; treatment program; volunteer

Specific Aims: Illicit and prescribed stimulants provide major challenges in the US. In a recent year, almost 7.5 million Americans reported cocaine or methamphetamine use. More than 32 million amphetamine prescriptions were written for disorders including attention deficit hyperactivity disorder and narcolepsy. 1.75 million Americans reported cocaine or amphetamine or use disorders. There were more than 212,000 admissions to stimulant use disorder treatment programs. A “fourth wave” of US drug overdose deaths includes many individuals who use stimulants. However, individuals who seek to quit stimulant use have no pharmacological treatment approved by FDA. Medication development portfolios aimed at treating stimulant use disorders should include new drugs acting at novel targets that are as well-supported as possible, a priori, by human and other data. Robust human, mouse model and pharmacologic data now support PTPRD (receptor type protein tyrosine phosphatase D) as a novel target for treatment of stimulant use disorders and, perhaps, their prevention. Human PTPRD genomic variants are associated with: a) vulnerability to develop a stimulant use disorder, b) the extent of reward from stimulant administration and c) levels of brain PTPRD expression. Mice that express less PTPRD display less reward from stimulants. We have characterized an initial PTPRD phosphatase inhibitor, 7-BIA, and a more potent/selective congener, NHB1109. NHB1109 features support its development as a medication. We can now synthesize NHB1109 readily from commercially-available precursors. NHB1109 is selective. It displays greater potency at PTPRD than at most other tyrosine phosphatases. It has no significant activity in EUROFINS screens of targets of current drugs. NHB1109 is bioavailable in rats after oral dosing. It is relatively stable. It has intellectual property protection. It substantially reduces cocaine conditioned place preference in wildtype mice, but not in PTPRD knockouts. Acute or repeated NHB1109 doses up to 300 mg/kg provide no toxicity. Mice survive 2,000 mg/kg gavage doses, but develop a dose-limiting toxicity, ileus. This exciting identification of NHB1109 as a novel, potent, selective small molecule PTPRD phosphatase inhibitor with proof of in vivo pharmacological activity in reducing stimulant reward and a reasonable therapeutic index leads us to seek Avant Garde support. We will move NHB1109 forward through IND-enabling work, initial use in humans and completion of phase I human studies. We will continue studies of backup compounds should NHB 1109 display unanticipated limitations. We will complete antecedents to FDA IND approval including metabolic, two-species toxicity and carcinogenicity screens. We will receive IND approval and complete first in human, ascending dose and repeated dose research volunteer studies, including those with amphetamine challenge doses. We will advance development of NHB1109 to address unmet needs in treating devastating stimulant use disorders via these UG3 and UH3 Aims: UG3 Aim 1: To develop pharmacologic and toxicologic evidence in vitro and in two species that robustly support an IND application for use of NHB1109 (or backup compounds if required) in normal human research volunteers. UG3 Aim 2: To develop pharmacologic and toxicologic evidence in two species that robustly support an IND application for use of challenge doses of stimulants along with NHB1109 in normal human research volunteers. Milestones for the end of the UG3 support period: Filing a successful FDA IND application for NHB1109 human use without, then with, amphetamine challenge doses. UH3 Aim 1: To complete good manufacturing practices syntheses, formulations for human use, ascending dose and repeated dose studies with monitoring of toxicities and pharmacokinetic/pharmacodynamic properties in normal human research volunteers. UH3 Aim 2: To complete repeated dose studies with challenge doses of amphetamine in normal human research volunteers with monitoring of toxicities and pharmacokinetic/pharmacodynamic properties in normal human research volunteers. To complete antecedents to longer use in humans. Milestones for the end of the UH3 period of support: Robust data on NHB1109 tolerability, toxicities and pharmacokinetics/pharmacodynamics in humans, some of whom also receive challenge doses of amphetamine. Initial pilot data for stimulant reward in NHB1109- vs placebo-treated research volunteers. These data will set the stage for subsequent and more definitive phase II work to test NHB1109 effects on reward from amphetamine and ability to maintain abstinence in treatment-seeking individuals with stimulant use disorders. The data will enable subsequent use in prevention studies. They will provide strong bases for further development of NHB1109 with continuing NIDA and pharma partnerships.

具体目标：非法和处方兴奋剂给美国带来了重大挑战。近一年来，几乎 750 万美国人报告使用可卡因或甲基苯丙胺。超过3200万安非他明 处方是针对注意力缺陷多动症和发作性睡病等疾病而开的。 1.75 数百万美国人报告可卡因或安非他明或使用障碍。人数超过 212,000 接受兴奋剂使用障碍治疗计划。美国药物过量死亡的“第四波” 包括许多使用兴奋剂的人。然而，寻求戒除兴奋剂使用的个人却没有 FDA批准的药物治疗。旨在治疗兴奋剂的药物开发组合 使用障碍应包括作用于新靶点的新药，这些靶点应得到尽可能充分的支持、先验、 通过人类和其他数据。 稳健的人类、小鼠模型和药理学数据现在支持 PTPRD（受体型蛋白酪氨酸） 磷酸酶 D）作为治疗兴奋剂使用障碍的新靶标，或许还可以预防它们。 人类 PTPRD 基因组变异与：a) 易患兴奋剂使用障碍，b) 兴奋剂管理的奖励程度和 c) 大脑 PTPRD 表达水平。表达的小鼠 较少的 PTPRD 显示来自兴奋剂的较少奖励。我们已经表征了初始 PTPRD 磷酸酶 抑制剂 7-BIA 和更有效/选择性更强的同系物 NHB1109。 NHB1109 的特性支持其作为药物的开发。我们现在可以很容易地合成 NHB1109 市售前体。 NHB1109 是选择性的。它在 PTPRD 上表现出的效力比最多 其他酪氨酸磷酸酶。它在 EUROFINS 对当前药物靶点的筛选中没有显着的活性。 口服给药后，NHB1109 在大鼠体内具有生物利用度。是比较稳定的。它具有知识产权保护。它 显着降低野生型小鼠中的可卡因条件性位置偏好，但在 PTPRD 敲除小鼠中则不然。 急性或重复高达 300 mg/kg 的 NHB1109 剂量不会产生毒性。小鼠灌胃 2,000 毫克/千克后存活 剂量，但会产生剂量限制性毒性，即肠梗阻。 NHB1109 被鉴定为一种新型、有效、选择性小分子 PTPRD 磷酸酶，这一令人兴奋的发现 具有减少刺激奖励的体内药理活性证据和合理的抑制剂 治疗指数引导我们寻求前卫的支持。我们将通过 IND 支持推动 NHB1109 向前发展 工作、首次在人类中使用并完成第一阶段人类研究。我们将继续研究备份 NHB 1109 化合物应表现出意想不到的局限性。我们将完成 FDA IND 的前因 批准包括代谢、两种毒性和致癌性筛选。我们将获得 IND 批准 并首先完成人体、剂量递增和重复剂量研究志愿者研究，包括那些 与安非他明挑战剂量。我们将推进 NHB1109 的开发，以满足未满足的需求 通过这些 UG3 和 UH3 目标治疗破坏性兴奋剂使用障碍： UG3 目标 1：在体外和两个物种中开发药理学和毒理学证据， 支持在正常人类研究中使用 NHB1109（或备用化合物，如果需要）的 IND 申请 志愿者。 UG3 目标 2：在两个物种中开发有力支持 IND 的药理学和毒理学证据 在正常人类研究志愿者中使用挑战剂量的兴奋剂和 NHB1109 的申请。 UG3 支持期结束的里程碑：成功提交 NHB1109 人类 FDA IND 申请 先不使用苯丙胺激发剂量，然后再使用苯丙胺激发剂量。 UH3 目标 1：完成良好生产规范合成、供人类使用的配方、提升 剂量和重复剂量研究，监测毒性和药代动力学/药效学 正常人类研究志愿者的特性。 UH3 目标 2：完成正常人体内苯丙胺挑战剂量的重复剂量研究 研究志愿者监测正常情况下的毒性和药代动力学/药效学特性 人类研究志愿者。完成在人类中长期使用的前因。 UH3 支持期结束的里程碑：关于 NHB1109 耐受性、毒性和安全性的可靠数据 人体药代动力学/药效学，其中一些人还接受攻击剂量 安非他明。 NHB1109 与安慰剂治疗的研究志愿者的刺激奖励的初步试点数据。 这些数据将为后续更明确的 II 期工作奠定基础，以测试 NHB1109 对 安非他明的奖励和使用兴奋剂寻求治疗的个体保持禁欲的能力 使用障碍。这些数据将使后续用于预防研究。他们将为 NIDA 与制药公司持续合作，进一步开发 NHB1109。