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，具有成瘾性，可迅速产生耐受性，损害运动表现，并且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样物质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σ-2受体结合的新化合物，我们将其鉴定为跨膜蛋白97（TMEM 97），其在神经性疼痛的动物模型中以高且持久的功效缓解疼痛，并且当重复给药时没有可观察到的耐受性。这些作用在Tmem 97敲除（KO）小鼠中不存在，证明了TMEM 97的小分子调节在体内的特异性。这些重要的发现代表了疼痛管理领域的突破，因为它为治疗神经性疼痛的全新方法打开了大门。所提出的优化程序的目标是鉴定至少一种IND使能的阳性TMEM 97调节剂来治疗神经性疼痛。我们将分两个不同的阶段实现这一目标。在UG 3阶段，我们将制备当前先导化合物rac-FEM 1689的亲脂性较低的类似物，以降低安全性责任，包括hERG活性，同时保留疗效、效价、TMEM 97亲和力和特异性以及生物利用度。这些优化研究将通过rac-FEM 1689类似物的合成和评价以迭代方式实现，并且包括确定：（1）TMEM 97亲和力;（2）人Caco-2细胞中的p-eIF 2a抑制，以评估阻断整合应激反应的激活的假定作用，已知整合应激反应与神经性疼痛相关;（3）水溶性;（4）hERG通道活性;（5）体外DMPK;（6）体内PK;（7）在大鼠骶神经损伤模型中的功效;和（8）在人背根神经节（DRG）神经元中的功效。这些研究将导致选择一种先导化合物和一种或多种备用化合物，以推进到下一阶段。在UH 3阶段，我们将在人DRG电生理学试验中检测先导化合物和备用化合物，以评估人DRG伤害感受器中尼古丁诱导的过度兴奋性的逆转。我们将使用SafetyScreen 87 CEEPS面板进行广泛筛选，并使用这些和其他PK数据来确定有效且脱靶效应概率最小的剂量范围。其他IND使能研究将包括筛选最佳盐形式和表征、临床前毒理学、完善GMP生产的合成路线、完成第一个中试批次以及分析方法开发和杂质谱测定。拟议的研究是重要的，因为它们将验证TMEM 97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TMEM 97调节剂作为开发候选物，通过具有低成瘾潜力的非阿片途径治疗神经性疼痛。