Novel treatment of posttraumatic stress disorder

创伤后应激障碍的新疗法

• 批准号: 9345127
• 负责人: Yvonne Y. Lai
• 金额: $ 137.31万
• 依托单位: ANAGIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345127
• 关键词: Address; Adult; Adverse effects; Affect; American; Amygdaloid structure; Animal Model; Anxiety Disorders; Attenuated; Back; Binding; Biochemical; Biological Assay; Biological Availability; Businesses; Chemical Structure; Chemicals; Chemistry; Chronic; Clinical; Clinical Trials; Complex; Coupling; Cues; Cyclic GMP-Dependent Protein Kinases; Development; Dose; Drug Kinetics; Enzyme Activation; Event; Exposure to; Extinction (Psychology); Financial compensation; Formulation; Generations; Genes; Glutamate Receptor; Glutamates; Goals; Grant; Guanylate Cyclase; Health Care Costs; Human; Hyperalgesia; In Vitro; Indiana; Investigational Drugs; Knock-out; Lead; Long-Term Potentiation; Maintenance; Medical; Memory; Memory impairment; Methods; Modeling; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase Type I; Oral; Parents; Pathological anxiety; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Post-Traumatic Stress Disorders; Pre-Clinical Model; Preclinical Drug Development; Preparation; Presynaptic Terminals; Prevention strategy; Principal Investigator; Process; Production; Property; Proteins; Receptor Activation; Receptor Signaling; Recruitment Activity; Research; Route; Scaffolding Protein; Secondary Prevention; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Symptoms; Synapses; Synaptic plasticity; Testing; Therapeutic; Toxicology; Trauma; Universities; Validation; Veterans; analog; base; clinical candidate; conditioned fear; cost; density; design; disability; drug candidate; drug development; drug testing; effective therapy; experience; functional disability; high throughput screening; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; motor impairment; neurotransmission; novel; phase 1 study; postsynaptic density protein; pre-clinical; protein protein interaction; psychologic; receptor; response; small molecule; small molecule inhibitor; socioeconomics; traumatic event; treatment of anxiety disorders

Project Summary The present application “Novel Treatment for Posttraumatic Stress Disorder” addresses the critical need for more efficacious treatments for posttraumatic stress disorder (PTSD). The excitatory neurotransmitter, glutamate, activates a key neural signaling cascade upon a trauma experience. In this activation, glutamate binds to and activates the NMDA receptor, a glutamate receptor subtype. Binding and activation triggers the formation of a complex at the receptor and leads to activation of the enzyme neuronal nitric oxide synthase (nNOS) and a concomitant increase in the production of the signaling molecule nitric oxide (NO). These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD. Postsynaptic density protein 95 (PSD95) targets nNOS to the NMDA receptor facilitating the formation of this signaling complex. PSD95 is therefore, required for NMDA receptor activation of nNOS. Lai, Anagin co-founder and principal investigator for this project, first showed that the small molecule, IC87201, disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Anagin, an Indiana-based small business and its preclinical team at Indiana University, led by Dr. Shekhar (co-founder of Anagin), has demonstrated that IC87201 and a related analog, ZL006, block the long-term encoding of conditioned fear even after a fear conditioning session has occurred (i.e. post- trauma). Unlike NMDA receptor antagonists, these protein interaction inhibitors are efficacious in suppressing PTSD-like symptoms in a well-established preclinical model without producing motor or memory impairment. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. In Anagin's successful SBIR Phase I studies, the team established positive structural-activity-relationship and demonstrated oral efficacy of its first-generation lead and identified a promising new chemical series. The goal of this Phase II SBIR is to deliver an orally available drug candidate and initiate IND-enabling studies delineated through two specific aims. Aim 1: Perform lead optimization studies to select a Drug Development Candidate. Aim 2: Validate the Drug Development Candidate in IND-enabling studies. A traditional drug medicinal chemistry approach will be used to design and develop novel analogs with improved pharmacokinetic properties and potency compared to the parent compounds. Anagin anticipates completion of initial IND-enabling studies at the end of the grant period. The development of effective pharmacotherapies with novel chemical structures that possess limited side-effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients. The ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in PTSD or anxiety disorders.

项目摘要 本申请“创伤后应激障碍的新治疗”解决了以下关键需求： 更有效的治疗创伤后应激障碍（PTSD）。兴奋性神经递质， 谷氨酸盐激活了创伤经历后的关键神经信号级联。在这种激活中，谷氨酸 结合并激活NMDA受体，一种谷氨酸受体亚型。绑定和激活触发 在受体处形成复合物，并导致神经元型一氧化氮合酶的激活 （nNOS）和伴随的信号分子一氧化氮（NO）产生的增加。这些事件 触发异常的突触可塑性，这与PTSD的启动和维持有关。突触后 密度蛋白95（PSD 95）将nNOS靶向NMDA受体，促进该信号传导的形成 复杂.因此，PSD 95是nNOS的NMDA受体活化所必需的。Lai，Anagin联合创始人， 该项目的首席研究员，首先表明，小分子，IC 87201，破坏了功能， nNOS和PSD 95之间的蛋白质-蛋白质相互作用在体外并减弱NMDA受体依赖性 体内痛觉过敏。Anagin是一家位于印第安纳州的小企业，它在印第安纳州大学的临床前团队， 由Shekhar博士（Anagin的联合创始人）领导的研究表明，IC 87201和相关的类似物ZL 006可以阻断 条件性恐惧的长期编码，即使在恐惧条件反射会话发生后（即， 创伤）。与NMDA受体拮抗剂不同，这些蛋白质相互作用抑制剂有效抑制NMDA受体。 在一个完善的临床前模型中出现PTSD样症状，而不产生运动或记忆障碍。 因此，信号区室化的破坏代表了开发新治疗的创新方法 治疗焦虑症副作用更少在Anagin成功的SBIR I期研究中， 建立了积极的构效关系，并证明了其第一代先导化合物的口服有效性 并确定了一个有前途的新化学系列。本阶段II SBIR的目标是提供一种口服有效的 候选药物，并启动通过两个具体目标划定的IND使能研究。目标1：执行电极导线 优化研究，以选择候选药物开发。目标2：加速药物开发 IND赋能研究的候选人。传统药物药物化学方法将用于设计和 开发与母体相比具有改善的药代动力学性质和效力的新型类似物 化合物. Anagin预计在赠款期结束时完成初始IND使能研究。的 开发具有有限副作用的新化学结构的有效药物疗法 预计将降低不断上升的医疗保健费用，并减轻创伤后应激障碍患者不必要的痛苦。 患者最终目标是FDA IND提交的PTSD或PTSD I期临床试验的候选药物， 焦虑症