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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的这种应用，“新型小分子镇痛药的开发调节nnos-nos1ap蛋白 - 蛋白质相互作用，“解决了对治疗慢性神经性疼痛的更有效药物的关键需求在美国影响约1.16亿人。当前的NSAID，类固醇，操作等止痛药 Gabapentin类似物已经记录并经常严重的副作用，在神经性疗法中有效不佳疼痛并仅在有限的患者子集中提供足够的缓解。因为它的流行率很高和贫穷治疗方案，慢性疼痛导致每年估计的社会经济成本为560-6.35亿美元我们。 NMDA受体（NMDAR）的激活中枢神经系统敏感性，即在神经性疼痛的发展和维持中实施。 NMDA介导的中央灵敏度取决于接收器的多蛋白级联复合物的形成，包括突触后密度95 蛋白质（PSD95），神经元一氧化氮合酶（NNOS）和NOS1衔接蛋白（NOS1AP）。 NMDAR多蛋白质复合物的破坏者在临床前中风和疼痛模型中有效，并且是目前正在缺血性中风的临床试验中。针对该络合物的小分子抑制剂具有潜力具有有效的镇痛药，而没有与NMDAR的广泛抑制有关的副作用。直接 NMDAR复合物的下游效应子是NNOS-NOS1AP。抑制这种复合物的化合物可能会有效地防止神经性疼痛，中风和慢性神经系统疾病沉淀或恶化通过过多的NMDAR活动。在资助的I阶段SBIR计划中，我们的团队运行了一个广泛的小分子高通量屏幕以鉴定NNOS-NOS1AP蛋白 - 蛋白质相互作用的抑制剂。后确认活性，选择性和初始给药 - 分布 - 代谢 - 毒性/毒性（ADME/T）在顶级铅的研究中，我们选择了两个类似药物的选择性NNOS-NOS1AP抑制剂，具有不同的脚手架体内研究。两种抑制剂在疼痛模型中均有效。我们对一个化学系列，确定选择性和效力的区域。在当前的提案中，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新型类似物与母体化合物相比，药代动力学特性和效力。 Anagin及其研究合作伙伴在Amri和印第安纳大学，将通过早期铅优化研究至少一系列。在除了提高效力和ADME/T属性，我们将证明最好的类似物正在作用细胞中的预期目标，在两个临床前疼痛模型中验证其活性，并评估其安全性关键行为模型。不符合我们设定标准的化合物将不会提前提前。我们期待与当前的止痛药相比，我们的铅化合物将具有更好的治疗指数。我们有一个团队业务，化学，生物学和体内科学专家，将这些系列推向领导优化并进入诊所以治疗慢性神经性疼痛。