Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic pain

发现和开发用于治疗神经性疼痛的新型甘氨酸转运蛋白 2 抑制剂

• 批准号: 10592522
• 负责人: Christopher L. Cioffi
• 金额: $ 45.52万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592522
• 关键词: Absence of pain sensation; Acute Pain; Adult; Adverse effects; Analgesics; Animal Model; Behavioral Model; Benchmarking; Binding; Biological Assay; Brain; Characteristics; Clinical Trials; Collection; Data; Development; Disinhibition; Dissociation; Dose; Dose-Limiting; Equilibrium; Exhibits; Formalin Tests; GLYT2; General Population; Glycine; Healthcare; Human; Impairment; In Vitro; Libraries; Ligation; Lipids; Lysine; Malignant Bone Neoplasm; Measures; Medical; Metabolic; Metabolism; Modeling; Morphine; Morphine Abuse; Motor; Mus; Nerve; Neuropathy; Nociception; Nociceptors; Oral; Pain; Pathologic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Property; Protocols documentation; Rattus; Recovery; Reflex action; Reporting; Reproducibility; Risk; Rodent Model; Role; Safety; Signal Transduction; Slice; Small Interfering RNA; Spinal; Spinal Cord; Synapses; Therapeutic Index; Tissues; Variant; absorption; abuse liability; analog; base; chronic neuropathic pain; chronic pain; cost; counterscreen; design; dorsal horn; economic cost; extracellular; improved; in vivo; inhibitor; knock-down; lead optimization; meetings; motor behavior; neurotransmission; novel; opioid sparing; pain behavior; pain model; pain reduction; pain relief; painful neuropathy; pre-clinical; presynaptic; productivity loss; side effect

It is estimated that 7–10% of the general population suffers from chronic neuropathic pain and associated annual economic costs exceed $160 billion in the US. Current analgesics used to treat chronic neuropathic pain lack efficacy, induce dose-limiting side effects or present a significant risk of tolerance and abuse. Thus, the discovery of novel analgesics that provide meaningful pain relief with improved safety, tolerability and reduced abuse potential remains an unmet medical need. Among the various mechanisms involved in pathological pain, disinhibition of nociceptive signaling from the spinal cord to the higher CNS plays a critical role. Indeed, we and others have shown that inhibitory glycinergic neurotransmission in the dorsal horn is impaired in pathological pain states. Thus, it has been proposed that enhancing spinal glycinergic neurotransmission could reduce nociceptor signaling and provide analgesia. Glycine transporter-2 (GlyT-2) regulates extracellular glycine concentrations in the CNS and presents a highly attractive target to augment impaired spinal inhibitory signaling. Indeed, GlyT-2 inhibitors have demonstrated efficacy in several rodent models of acute and chronic pain. Recent studies suggest that either partial or reversible GlyT-2 inhibition can potentially circumvent potential mechanism-based adverse effects and provide analgesics with a suitable balance of efficacy and tolerability. We synthesized 60 bioactive lipid allosteric partial inhibitors exhibiting varying degrees of potency and %maximal inhibition and our most potent compound of this class enhances tonic glycinergic currents ex vivo in rat spinal cord slices without depleting presynaptic glycine reloading and produces in vivo dose-dependent efficacy in PNL rats without adverse effects. Separately, we synthesized 18 novel GlyT-2 inhibitor hit compounds derived from ORG-25543 that exhibit reproducible variations in reversibility and transport recovery using a washout assay protocol. From these two libraries, we propose conducting a dual-pronged medicinal chemistry campaign to identify optimized compounds possessing favorable potency, binding profiles and ADME characteristics suitable for measuring effects in spinal cord slices and in vivo PK. Selected compounds will be screened in the rat PNL model to assess analgesic efficacy and in behavioral models for dose-limiting effects and TI. Our proposal seeks support to optimize our hit compounds to provide selective and orally bioavailable GlyT-2 inhibitors for further development and eventual human clinical trials in neuropathic pain. The studies outlined in this proposal seek to conduct medicinal chemistry optimization using a battery of primary, secondary, counter-screen, and ADMET assays to assess potency, binding profile (%maximal inhibition, reversibility and mechanism of binding), selectivity and drug- like properties (Specific Aim 1), and assess PK, preclinical analgesic efficacy and tolerability of advanced compounds in animal models of neuropathic pain and motor behavior at different stages of compound optimization (Specific Aim 2).

据估计，7%-10%的普通人群患有慢性神经病理性疼痛和与之相关的 美国每年的经济成本超过1600亿美元。目前用于治疗慢性神经病的止痛药 疼痛缺乏疗效，引起剂量限制的副作用，或存在耐受性和滥用的重大风险。因此， 新型止痛药的发现，可提供有意义的止痛，并提高安全性、耐受性和 减少滥用的可能性仍然是一个未得到满足的医疗需求。在涉及的各种机制中， 病理性疼痛，解除对脊髓至较高中枢神经系统伤害性信号的抑制起着关键作用 角色。事实上，我们和其他人已经证明，在背角中抑制甘氨酸能神经传递是 在病理性疼痛状态下受损。因此，有人提出了增强脊髓甘氨酸能 神经传递可减少伤害性感受器信号，提供镇痛作用。甘氨酸转运蛋白2(GlyT-2) 调节中枢神经系统细胞外甘氨酸浓度，并呈现一个极具吸引力的增强靶点 脊髓抑制信号受损。事实上，GlyT-2抑制剂已经在几种啮齿动物身上证明了有效性 急性和慢性疼痛模型。最近的研究表明，部分或可逆的GlyT-2抑制 可以潜在地规避潜在的基于机制的不良反应，并为止痛药提供适当的 在有效性和耐受性之间取得平衡。我们合成了60种具有生物活性的脂类变构部分抑制剂。 不同程度的效力和最大抑制率，以及我们这类最有效的化合物增强了 大鼠脊髓脑片紧张性甘氨酸能电流不耗竭突触前甘氨酸再负荷和 在PNL大鼠体内产生剂量依赖的疗效，没有不良反应。另外，我们合成了 18种来源于ORG-25543的新型GlyT-2抑制剂HIT化合物，在 使用洗脱分析方案的可逆性和传输恢复。从这两个库中，我们建议 开展双管齐下的药物化学活动，以确定具有以下特性的优化化合物 适用于测量脊髓效应的良好效力、结合谱和ADME特征 切片和体内PK。将在大鼠PNL模型中筛选选定的化合物以评估止痛效果 以及在剂量限制效应和TI的行为模型中。我们的建议寻求支持以优化我们的成功 化合物为进一步开发和最终提供选择性和口服生物利用的GlyT-2抑制剂 神经病理性疼痛的人类临床试验。这项提案中概述的研究试图进行药物治疗 使用一系列初级、次级、反筛选和ADMET分析来评估化学优化 效力、结合谱(最大抑制率、可逆性和结合机制)、选择性和药物- 相似属性(特异性1)，并评估PK、临床前镇痛疗效和对晚期患者的耐受性 神经病理性疼痛动物模型中的化合物及其不同阶段的运动行为 优化(具体目标2)。

项目成果

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling.

• DOI: 10.3390/biom11060864
• 发表时间: 2021-06-10
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Cioffi CL

Glycine Transporter 2: Mechanism and Allosteric Modulation.

• DOI: 10.3389/fmolb.2021.734427
• 发表时间: 2021
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Frangos ZJ;Cantwell Chater RP;Vandenberg RJ
• 通讯作者: Vandenberg RJ

Opioid overdose and tolerance: is the recruitment of β-arrestin to the µ-receptor involved?

阿片类药物过量和耐受性：是否涉及β-抑制蛋白向μ-受体的募集？

• DOI: 10.1038/s41386-021-01121-3
• 发表时间: 2021
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Gillis,Alexander;Christie,MacdonaldJ
• 通讯作者: Christie,MacdonaldJ