Development of positive TMEM97 modulators for treating neuropathic pain

开发用于治疗神经性疼痛的正 TMEM97 调节剂

• 批准号: 10642506
• 负责人: STEPHEN MARTIN
• 金额: $ 135.22万
• 依托单位: NUVONURO INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642506
• 关键词: Affect; Afferent Neurons; Affinity; American; Analgesics; Animal Model; Area; Binding; Biological; Biological Assay; Biological Availability; Caco-2 Cells; Chronic; Clinical; Clinical Treatment; Data; Development; Dose; Electrophysiology (science); Eukaryotic Initiation Factors; Evaluation; Female; Formulation; Genes; Goals; Human; Hypersensitivity; Image; In Vitro; Injury; Integral Membrane Protein; Knockout Mice; Lead; Letters; Ligands; Link; Measurement; Measures; Mechanics; Microsomes; Modeling; Mus; Neurons; Nociceptors; Opioid; Oral; Organ Donor; Outcome; Pain; Pain management; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Phosphorylation; Polymorph; Population; Positioning Attribute; Price; Probability; Process; Property; Rattus; Recording of previous events; Research; Research Personnel; Rodent Model; Role; Route; Safety; Series; Sodium Chloride; Solubility; Specificity; Spinal Ganglia; Stress Response Signaling; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Toxicology; Trauma; United States; Work; Writing; addiction liability; analog; analytical method; aqueous; austin; biological adaptation to stress; chemotherapy; chronic pain; clinical candidate; cytokine; design; diabetic; duloxetine; enantiomer; experimental study; gabapentin; improved; in vivo; lipophilicity; male; manufacture; method development; motor impairment; mouse model; nerve injury; non-opioid analgesic; novel; novel strategies; novel therapeutics; pain model; pain relief; painful neuropathy; pre-clinical; programs; receptor; screening; sigma-2 receptor; small molecule; small molecule libraries; spared nerve; standard of care; treatment optimization

Nearly a third of Americans suffer from chronic pain, but opioids, which are the most commonly used pain reliev- ers, are addictive, rapidly produce tolerance, impair motor performance, and are of limited efficacy for neuro- pathic pain. There is thus an urgent unmet need for the discovery and development of novel drugs that alleviate neuropathic pain through non-opioid and non-addicting mechanisms. We recently discovered several novel com- pounds that bind to the sigma-2 receptor, which we identified as transmembrane protein 97 (TMEM97), that relieve pain in an animal model of neuropathic pain with high and lasting efficacy and with no observable toler- ance when dosed repeatedly. These effects are absent in Tmem97 knockout (KO) mice, demonstrating the specificity of small molecule modulation of TMEM97 in vivo. These significant findings represent a breakthrough in the area of pain management because it opens the door to a completely new approach to treat neuropathic pain. The goal of the proposed optimization program is to identify at least one IND-enabled, positive TMEM97 modulator to treat neuropathic pain. We will achieve this goal in two distinct phases. In the UG3 Phase, we will prepare less lipophilic analogs of our current lead rac-FEM1689 to reduce safety liabilities, including hERG ac- tivity, while retaining efficacy, potency, TMEM97 affinity and specificity, and bioavailability. These optimization studies will be achieved in an iterative fashion by the synthesis and evaluation of analogs of rac-FEM1689 and involve determining: (1) TMEM97 affinities; (2) p-eIF2a inhibition in human Caco-2 cells to assess the putative role of blocking activation of the integrated stress response, which is known to be associated with neuropathic pain; (3) aqueous solubility (4) hERG channel activity; (5) in vitro DMPK; (6) in vivo PK; (7) efficacy in the rat Spared Nerve Injury model; and (8) efficacy in human dorsal root ganglion (DRG) neurons. These studies will result in the selection of a lead compound and one or more backup compounds for advancement to the next phase. In the UH3 Phase, we will test the lead and backup compounds in the human DRG electrophysiology assay to assess reversal of cytokine-induced hyperexcitability in human DRG nociceptors. We will conduct broad screens with the SafetyScreen87 CEREPS panel and use these and other PK data to determine a dose range where there is efficacy with minimal probability of off-target effects. Other IND-enabling studies will include screening for optimal salt form and characterization, preclinical toxicology, refinement of the synthetic route for GMP manufacturing, completion of the first pilot batch, as well as analytical method development and determination of impurity profile. The proposed studies are significant because they will validate TMEM97 as a new target for developing drugs that relieve neuropathic pain, and they will lead to the discovery of at least one positive TMEM97 modulator as a development candidate to treat neuropathic pain by a non-opioid pathway with low addiction potential.

近三分之一的美国人患有慢性疼痛，但阿片类药物是最常用的止痛药，容易上瘾，迅速产生耐受性，损害运动表现，对神经性疼痛的疗效有限。因此，迫切需要发现和开发通过非阿片类药物和非成瘾机制减轻神经性疼痛的新型药物。我们最近发现了几种与sigma-2受体结合的新型化合物，我们将其确定为跨膜蛋白97 (TMEM97)，可以缓解神经性疼痛动物模型的疼痛，具有高且持久的疗效，并且在重复给药时没有明显的耐受性。这些作用在Tmem97敲除（KO）小鼠中不存在，证明了Tmem97在体内的小分子调节的特异性。这些重要的发现代表了疼痛管理领域的一个突破，因为它为神经性疼痛的全新治疗方法打开了大门。所提出的优化方案的目标是确定至少一种ind激活的阳性TMEM97调节剂来治疗神经性疼痛。我们将分两个阶段实现这一目标。在UG3阶段，我们将制备目前的race - fem1689的亲脂性较低的类似物，以降低安全性，包括hERG活性，同时保持功效、效力、TMEM97亲和力和特异性以及生物利用度。这些优化研究将通过rac-FEM1689类似物的合成和评估以迭代的方式实现，并涉及确定：(1)TMEM97亲和性；(2)人类Caco-2细胞中的p-eIF2a抑制，以评估阻断综合应激反应激活的假定作用，已知其与神经性疼痛相关；(3)水溶性(4)hERG通道活性；(5)体外DMPK；(6)体内PK；(7)对大鼠备用神经损伤模型的疗效；(8)对人背根神经节（DRG）神经元的作用。这些研究将导致先导化合物和一种或多种备用化合物的选择，以推进到下一阶段。在UH3阶段，我们将在人DRG电生理实验中测试先导化合物和备用化合物，以评估细胞因子诱导的人DRG伤害感受器的高兴奋性逆转。我们将使用SafetyScreen87 CEREPS面板进行广泛筛选，并使用这些和其他PK数据来确定具有最小脱靶效应可能性的有效性的剂量范围。其他支持ind的研究将包括筛选最佳盐形态和特征、临床前毒理学、改进GMP生产的合成路线、完成第一批中试产品，以及分析方法的开发和杂质谱的确定。这些研究具有重要意义，因为它们将验证TMEM97作为开发缓解神经性疼痛药物的新靶点，并且它们将导致发现至少一种阳性的TMEM97调节剂作为开发候选物，通过低成瘾潜力的非阿片类药物途径治疗神经性疼痛。