PTPRD phosphatase inhibitors for stimulant use disorders

具体目标：非法和处方兴奋剂在美国构成重大挑战。在最近一年，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 医生为包括注意力缺陷多动障碍和发作性睡病在内的疾病开出了处方。1.75 据报道，有数百万美国人患有可卡因、安非他明或吸毒障碍。当时有超过21.2万人 接受兴奋剂使用障碍治疗计划。美国吸毒过量死亡的“第四波” 包括许多使用兴奋剂的个人。然而，寻求戒除兴奋剂使用的个人并没有 FDA批准的药物治疗。旨在治疗兴奋剂的药物开发组合 使用障碍应该包括作用于新靶点的新药，这些新药事先得到了尽可能好的支持， 通过人类和其他数据。 强大的人类、小鼠模型和药理学数据现在支持PTPRD(受体类型蛋白酪氨酸 磷酸酶D)作为治疗兴奋剂使用障碍和预防的新靶点。 人类PTPRD基因组变异与：a)易患兴奋剂使用障碍，b) 给予刺激剂的奖励程度和c)脑中PTPRD的表达水平。表达的小鼠 PTPRD越少，从兴奋剂中获得的奖励越少。我们已经鉴定了一种初始的PTPRD磷酸酶 抑制剂7-BIA和更有效/选择性更强的同系物NHB1109。 NHB1109的特点支持其作为药物的发展。我们现在可以很容易地合成NHB1109 商业上可获得的前体。NHB1109具有选择性。它在PTPRD表现出比至多 其他酪氨酸磷酸酶。它在Eurofins对当前药物靶标的筛选中没有显着的活动。 大鼠口服NHB1109后生物利用度较高。是比较稳定的。它有知识产权保护。它 显著降低野生型小鼠的可卡因条件性位置偏爱，但在PTPRD基因敲除小鼠中不能。 急性或重复剂量高达300毫克/公斤的NHB1109没有毒性。2,000 mg/kg灌胃小鼠存活 剂量，但会产生限制剂量的毒性，肠梗阻。 NHB1109是一种新的、有效的、选择性的小分子PTPRD磷酸酶 具有体内减少兴奋奖赏的药理活性且合理的抑制剂 治疗指数引导我们寻求前卫的支持。我们将通过启用IND来推动NHB1109向前发展 工作，在人体上的初步使用，并完成第一阶段人体研究。我们将继续研究后备 化合物应显示NHB 1109未预料到的限制。我们将完成FDA Ind的前言 批准包括新陈代谢、两种毒性和致癌性筛选。我们将获得IND批准 并在人体、递增剂量和重复剂量研究志愿者研究中获得第一名，包括 安非他命挑战剂量。我们将推进NHB1109的开发，以解决未得到满足的需求 通过这些UG3和UH3目标治疗毁灭性的兴奋剂使用障碍： UG3目标1：在体外和在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NHB1109(或备用化合物)的IND应用程序 志愿者。 UG3目标2：在两种有力支持IND的物种中开发药理学和毒理学证据 与NHB1109一起在正常人研究志愿者中使用挑战剂量兴奋剂的申请。 UG3支持期结束的里程碑：为NHB1109人提交成功的FDA IND申请 不使用安非他明，然后使用安非他明挑战剂量。 UH3目标1：完成良好制造规范的综合，人类使用的配方，提升 毒性和药代动力学/药效学监测的剂量和重复剂量研究 正常人类研究志愿者的特性。 UH3目标2：在正常人中完成苯丙胺挑战剂量的重复剂量研究 正常受试者的毒副作用和药代动力学/药效学性质监测 人类研究志愿者。完成先行词在人类中更长时间的使用。 UH3支持期结束的里程碑：关于NHB1109耐受性、毒性和 人体药代动力学/药效学，其中一些人还接受挑战剂量的 安非他命。NHB1109-VS安慰剂治疗的研究志愿者的刺激性奖励的初步试点数据。 这些数据将为后续更明确的第二阶段工作奠定基础，以测试NHB1109对 安非他明的奖励和使用兴奋剂寻求治疗的个人维持戒断的能力 使用障碍。这些数据将使随后的预防研究得以使用。它们将为 与NIDA和制药公司继续合作，进一步开发NHB1109。

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.