PTPRD phosphatase inhibitors for stimulant use disorders

具体目标：非法和规定的兴奋剂在美国构成重大挑战。近一年来，几乎 7.5 100万美国人报告使用可卡因或甲基苯丙胺。超过3200万的安非他明 处方是针对包括注意力缺陷多动障碍和嗜睡症在内的疾病而开的。1.75 100万美国人报告可卡因或安非他明或使用障碍。有超过212，000人 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，寻求停止使用兴奋剂的人没有 FDA批准的药物治疗。药物开发组合旨在治疗兴奋剂 药物使用障碍应包括作用于新靶点的新药，这些新药应尽可能得到充分支持，先验， 人类和其他数据。 强大的人类，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点，并可能用于其预防。 人类PTPRD基因组变异与以下因素相关：a）易发生兴奋剂使用障碍，B） 来自兴奋剂施用的奖励程度和c）脑PTPRD表达水平。小鼠表达 PTPRD越少，来自兴奋剂的奖励越少。我们已经表征了初始PTPRD磷酸酶 抑制剂7-BIA和更有效/选择性的同源物NHB 1109。 NHB 1109的特性支持其作为药物的发展。我们现在可以很容易地合成NHB 1109， 市售的前体。NHB 1109具有选择性。它在PTPRD显示出比大多数 其他酪氨酸磷酸酶。它在EUROFINS筛选当前药物的靶点中没有显著活性。 大鼠经口给药后，NHB 1109具有生物利用度。它相对稳定。它有知识产权保护。它 在野生型小鼠中，可卡因条件性位置偏好显着降低，但在PTPRD基因敲除小鼠中则不然。 高达300 mg/kg的急性或重复NHB 1109剂量没有毒性。小鼠在2，000 mg/kg灌胃后存活 剂量，但发展剂量限制性毒性，肠梗阻。 NHB 1109作为一种新型、强效、选择性小分子PTPRD磷酸酶的令人兴奋的鉴定 抑制剂，其在降低刺激性奖赏中具有体内药理学活性， 治疗指数引导我们寻求先锋派的支持。我们将通过IND使能推动NHB 1109向前发展 工作、首次用于人体并完成第一阶段人体研究。我们将继续研究备份 化合物应NHB 1109显示意外的限制。我们将完成FDA IND的先决条件 批准包括代谢、两种毒性和致癌性筛查。我们将获得IND批准 并首次完成人体、递增剂量和重复剂量研究志愿者研究，包括 安非他明挑战剂量。我们将推进NHB 1109的开发，以解决未满足的需求， 通过这些UG 3和UH 3目标治疗毁灭性的兴奋剂使用障碍： UG 3目的1：在体外和两个物种中开发药理学和毒理学证据， 支持在正常人体研究中使用NHB 1109（或备用化合物，如需要）的IND申请 志愿者 UG 3目的2：在两个种属中开发药理学和毒理学证据，以有力支持IND 在正常人类研究志愿者中使用激发剂量的兴奋剂沿着NHB 1109的申请。 UG 3支持期结束的里程碑：成功提交NHB 1109人用FDA IND申请 先不使用安非他明挑战剂量，然后使用安非他明挑战剂量。 UH 3目标1：完成良好生产规范合成，人用制剂， 监测毒性和药代动力学/药效学的剂量和重复给药研究 正常人类研究志愿者的特性。 UH 3目的2：完成正常人中安非他明激发剂量的重复给药研究 研究志愿者的毒性和药代动力学/药效学特性监测正常 人类研究志愿者完成人类长期使用的前提。 UH 3支持期结束的里程碑：关于NHB 1109耐受性、毒性和 在人体中的药代动力学/药效学，其中一些人还接受了激发剂量的 安非他明NHB 1109与安慰剂治疗的研究志愿者中刺激性奖励的初步试验数据。 这些数据将为后续和更明确的第二阶段工作奠定基础，以测试NHB 1109对 安非他明的奖赏和寻求治疗的兴奋剂患者保持戒断的能力 使用障碍。这些数据将有助于随后在预防研究中使用。它们将为以下方面提供坚实的基础： NHB 1109的进一步发展与持续的NIDA和制药伙伴关系。

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.