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

基本信息

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
项目类别：
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

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

展开

项目摘要

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缓解疼痛，是成瘾性的，迅速产生耐受性，损害运动性能，并且对神经病情疼痛的疗效有限。因此，紧急未满足的需要发现和开发新型药物，这些药物通过非阿片类药物和非成瘾机制减轻神经性疼痛。我们最近发现了几种与Sigma-2受体结合的新型综合体，我们将其确定为跨膜蛋白97（TMEM97），可缓解具有高功效的神经性疼痛动物模型中的疼痛，并且在重复施加时没有可观察到的耐受性。这些作用在TMEM97敲除（KO）小鼠中不存在，这证明了体内TMEM97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突破，因为它为治疗神经性疼痛的全新方法打开了大门。拟议的优化程序的目的是识别至少一个索引的阳性TMEM97调节剂来治疗神经性疼痛。我们将以两个不同的阶段实现这一目标。在UG3阶段，我们将对当前铅RAC-FEM1689的亲脂性类似物的准备较少，以降低安全责任，包括HERG的能力，同时保持疗效，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迭代方式来实现RAC-FEM1689的类似物的合成和评估，并涉及确定：（1）TMEM97亲和力；（2）在人Caco-2细胞中抑制P-EIF2A，以评估阻断综合应激反应激活的推定作用，这已知与神经性疼痛有关；（3）水溶性（4）HERG通道活动；（5）体外DMPK；（6）体内PK；（7）在大鼠中保存神经损伤模型的功效；（8）人体背根神经（DRG）神经元的功效。这些研究将导致选择铅化合物和一种或多种备用化合物，以发展到下一阶段。在UH3阶段，我们将测试人类DRG电生理学测定法中的铅和备份化合物，以评估人DRG伤害感受器中细胞因子诱导的过度兴奋性的逆转。我们将使用SafetyScreen87少量面板进行广泛的筛选，并使用这些和其他PK数据来确定具有疗效的剂量范围，而脱靶效应的可能性最小。其他辅助研究将包括筛查最佳盐形式和表征，临床前毒理学，GMP制造的合成途径的完善，第一个试验批次的完成以及分析方法的开发以及杂质概况的确定。拟议的研究之所以重要，是因为它们将验证TMEM97作为缓解神经性疼痛的药物的新靶标，并且会导致发现至少有一个阳性TMEM97调节剂，作为通过低成瘾潜力的非阿片类药物途径来治疗神经性疼痛的发育候选者。