Development of positive TMEM97 modulators for treating neuropathic pain

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，会使人上瘾，迅速产生耐受性，损害运动能力，对神经性疼痛的疗效有限。因此，发现和开发通过非阿片类药物和非成瘾机制缓解神经病理性疼痛的新药的需求迫切而未得到满足。我们最近发现了几种新的与sigma-2受体结合的化合物，我们将其鉴定为跨膜蛋白97(TMEM97)，在神经病理性疼痛的动物模型中具有高而持久的止痛效果，重复给药没有观察到的耐受性。这些效应在Tme97基因敲除(KO)小鼠中是不存在的，表明了TMEM97在体内小分子调控的特异性。这些重要的发现代表着疼痛管理领域的突破，因为它打开了治疗神经性疼痛的全新方法的大门。建议的优化计划的目标是确定至少一种IND启用的、阳性的TMEM97调节剂来治疗神经病理性疼痛。我们将分两个不同的阶段实现这一目标。在UG3阶段，我们将制备我们目前领先的RAC-FEM1689的亲脂性较低的类似物，以减少安全隐患，包括HERG活性，同时保持有效性、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合成和评估RAC-FEM1689类似物以迭代方式实现，涉及确定：(1)TMEM97亲和力；(2)对人Caco-2细胞的p-eIF2a抑制，以评估已知与神经病理性疼痛有关的综合应激反应的阻断激活的可能作用；(3)水溶解性(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)神经元的疗效。这些研究将导致选择一种先导化合物和一种或多种后备化合物，以进入下一阶段。在UH3阶段，我们将测试人类DRG电生理学测试中的先导和后备化合物，以评估细胞因子诱导的人类DRG伤害性感受器过度兴奋的逆转。我们将使用SafetyScreen87 CEREPS面板进行广泛的筛查，并使用这些和其他PK数据来确定具有疗效且偏离目标的可能性最小的剂量范围。其他支持IND的研究将包括筛选最佳盐形式和特性、临床前毒理学、改进GMP制造的合成路线、完成第一批中试，以及分析方法的开发和杂质分布的测定。拟议的研究具有重要意义，因为它们将验证TMEM97作为开发缓解神经病理性疼痛药物的新靶点，并将导致发现至少一个阳性TMEM97调节剂作为开发候选药物，通过低成瘾潜力的非阿片类药物途径治疗神经病理性疼痛。

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.