Development of novel small molecule analgesics modulating the nNOS-NOS1AP protein-protein interaction

开发调节 nNOS-NOS1AP 蛋白-蛋白相互作用的新型小分子镇痛药

• 批准号: 10016857
• 负责人: STEPHANIE K FLORIO
• 金额: $ 28.61万
• 依托单位: ANAGIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016857
• 关键词: Adaptor Signaling Protein; Address; Affect; American; Analgesics; Behavioral; Binding; Biochemical; Biological Assay; Biology; Brain; Businesses; Cells; Chemicals; Chemistry; Clinic; Clinical Trials; Complex; Development; Drug Kinetics; Drug Targeting; Excretory function; Exhibits; Formalin; Freund' s Adjuvant; Funding; Goals; Grant; Healthcare Systems; High Prevalence; Hyperalgesia; In Vitro; Indiana; Ischemic Stroke; Lead; Ligation; Maintenance; Manuscripts; Mediating; Membrane; Metabolism; Modeling; Multiprotein Complexes; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NOS1 gene; Nerve Degeneration; Neuraxis; Neurons; Nitric Oxide Synthase Type I; Non-Steroidal Anti-Inflammatory Agents; Opioid; Pain; Pain management; Parents; Pathologic Processes; Patients; Penetration; Peptides; Persistent pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Pre-Clinical Model; Property; Proteins; Research; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Steroids; Stroke; Structure; Structure-Activity Relationship; Synapses; Therapeutic; Therapeutic Index; Toxic effect; Treatment Efficacy; Triage; United States; Universities; Ventilatory Depression; Work; analog; base; central sensitization; chronic neurologic disease; chronic neuropathic pain; chronic pain; cost; cost estimate; density; design; efficacy testing; gabapentin; health care availability; high throughput screening; improved; in vivo; in vivo Model; inhibitor/antagonist; lead optimization; lead series; mouse model; neuropsychiatry; novel; pain behavior; pain model; painful neuropathy; patient subsets; pre-clinical; prevent; programs; protein protein interaction; receptor; recruit; safety study; scaffold; sciatic nerve; side effect; small molecule; small molecule inhibitor; socioeconomics; stroke model; tool

Abstract This application, “Development of novel small molecule analgesics modulating the nNOS-NOS1AP protein- protein interaction,” addresses the critical need for more effective medications to treat chronic neuropathic pain affecting ~116 million people in the United States. Current pain medications such as NSAIDS, steroids, opiates and gabapentin analogs have documented and often severe side effects, are poorly effective in neuropathic pain and provide adequate relief only in limited subsets of patients. Because of its high prevalence and poor treatment options, chronic pain results in socioeconomic costs estimated at $560-635 billion annually in the US. Activation of NMDA receptors (NMDARs) mediates central nervous system sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor that includes post-synaptic density 95 protein (PSD95), neuronal nitric oxide synthase (nNOS) and NOS1 adaptor protein (NOS1AP). A peptide disruptor of the NMDAR multi-protein complex is efficacious in preclinical stroke and pain models and is currently in clinical trials for ischemic stroke. Small molecule inhibitors targeting this complex have the potential to be effective analgesics without the side effects associated with broad inhibition of NMDARs. A direct downstream effector of the NMDAR complex is nNOS-NOS1AP. A compound inhibiting this complex will likely be efficacious against neuropathic pain, stroke and chronic neurological diseases precipitated or exacerbated by excessive NMDAR activity. In the funded Phase I SBIR program, our team ran an extensive small molecule high-throughput screen to identify inhibitors of the nNOS-NOS1AP protein-protein interaction. After confirmation of activity, selectivity and initial administration-distribution-metabolism-excretion/toxicity (ADME/T) studies on the top leads, we chose two drug-like, selective nNOS-NOS1AP inhibitors with distinct scaffolds for in vivo studies. Both inhibitors are efficacious in pain models. We initiated a small chemistry effort on one chemical series, identifying regions for selectivity and potency. In the current proposal, 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 and its research partners at AMRI and Indiana University will advance at least one series through early lead optimization studies. In addition to improving potency and ADME/T properties, we will demonstrate that the best analogs are acting on the intended target in cells, validate their activity in two preclinical pain models and assess their safety profile in key behavioral in vivo models. Compounds that do not meet our set criteria will not be advanced. We anticipate that our lead compound would have a better therapeutic index than current pain medications. We have a team of business, chemistry, biology and in vivo scientific experts in place to advance these series towards lead optimization and into the clinic for the treatment of chronic neuropathic pain.

摘要 这项申请，“开发新型小分子镇痛剂调节nNOS-NOS 1AP蛋白- 蛋白质相互作用”，解决了更有效的药物治疗慢性神经性疼痛的迫切需要 影响了美国约1.16亿人。目前使用的止痛药，如NSAIDS、类固醇、阿片类药物 和加巴喷丁类似物有记录的并且通常是严重的副作用，在神经性疾病中效果差， 疼痛，仅在有限的患者亚群中提供充分的缓解。由于其患病率高且发病率低， 治疗选择，慢性疼痛导致的社会经济成本估计为560 -635十亿美元，每年在 我们NMDA受体（NMDAR）的激活介导中枢神经系统敏化，其是神经系统的一部分。 与神经性疼痛的发展和维持有关。NMDA介导的中枢敏化 依赖于受体上多蛋白级联复合物的形成，包括突触后密度95 蛋白（PSD 95）、神经元型一氧化氮合酶（nNOS）和NOS 1衔接蛋白（NOS 1AP）。的肽 NMDAR多蛋白复合物的破坏剂在临床前中风和疼痛模型中有效， 目前正在进行缺血性中风的临床试验针对这种复合物的小分子抑制剂具有潜力 是有效的镇痛剂，而没有与广泛抑制NMDAR相关的副作用。直接 NMDAR复合物的下游效应物是nNOS-NOS 1AP。抑制这种复合物的化合物可能会 有效对抗神经性疼痛、中风和慢性神经疾病的加重或恶化 过量的NMDAR活性在资助的第一阶段SBIR计划中，我们的团队运行了广泛的小分子 高通量筛选以鉴定nNOS-NOS 1AP蛋白-蛋白相互作用的抑制剂。后 活性、选择性和初始给药-分布-代谢-排泄/毒性（ADME/T）确认 在对最重要的研究中，我们选择了两种具有不同支架的药物样选择性nNOS-NOS 1AP抑制剂， 体内研究。两种抑制剂在疼痛模型中均有效。我们开始了一个小的化学努力， 化学系列，确定区域的选择性和效力。在目前的提案中，一种传统药物 药物化学方法将用于设计和开发具有改进的 与母体化合物相比，药物代谢动力学性质和效力。Anagin及其研究伙伴 在AMRI和印第安纳州大学将推进至少一个系列通过早期铅优化研究。在 除了提高效力和ADME/T特性外，我们还将证明最好的类似物作用于 细胞中的预期靶点，在两种临床前疼痛模型中验证其活性，并评估其在 关键的体内行为模型。不符合我们设定标准的化合物将不会被推进。我们预计 我们的先导化合物将比目前的止痛药有更好的治疗指数。我们有一个团队 商业，化学，生物学和体内科学专家的到位，以推动这些系列走向领先 优化并进入临床用于治疗慢性神经性疼痛。