Analgesics Targeting TRPA1 for Treatment of Chronic Pain

描述(由申请人提供)： 标题：靶向TRPA1的止痛药用于治疗慢性疼痛摘要：一种有效的治疗慢性疼痛的药物，它既没有成瘾的潜力，也没有滥用的可能性，是当今医学中一个主要的未满足的需求。这些局限性推动了对基于新分子机制的新治疗选择的需求。我们的目标是发现和开发一种新型的、一流的治疗性小分子化合物，它是TRPA1(瞬时受体潜力，A亚家族，成员1)的功能拮抗剂，用于治疗慢性疼痛。TRPA1受体/通道在感觉神经中发挥着高度特异性的功能，这些感觉神经在炎症和神经损伤时传递疼痛和痛敏的感觉。由于TRPA1是感觉性伤害性感受器中最重要的疼痛信号整合因子之一，靶向TRPA1是在神经处理的第一阶段阻断伤害性信号的合乎逻辑的方法。TRPA1拮抗剂将作为外周作用的止痛剂发挥作用，因此被设计为没有成瘾和滥用潜力。阿尔格米迪克斯采用了一种创新的理性药理学方法，该方法已被证明能够识别多种新的化学支架，其效力相当于已建立的TRPA1配体。阿尔格米迪克斯使用动力学选择性图谱方法来表征药物作用，这导致了TRPA1的新的药理类别的识别。我们的方法可以识别TRPA1的经典拮抗剂、脱敏激动剂、反向激动剂和变构调节剂。目标1将基于新发现的3个TRPA1配体活性支架合成一组30个新颖的、可申请专利的结构类似物。我们将启动药物化学努力，以提高先导效力、选择性优化，并建立结构活性关系(SAR)分析。目标2将确定新化合物的效力、在人和大鼠体内的药理活性、激活和/或致敏的动力学。目的3是使用一组使用TRPV1、TRPV3和TRPM8的相关Trp通道来确定药理选择性：目的4是确定使用背根节(DRG)细胞的药理学活性：动力学、同源TRPA1脱敏和与TRPV1的交叉脱敏。TRPA1拮抗剂活性的靶细胞是感觉神经元。我们将使用分散的DRG神经元的短期培养来检测药物对感觉神经元内天然TRPA1通道的影响，以确认生理学相关性。第一阶段的最后一个里程碑是提供先进的先导分子和后备化合物，它们具有提名进入第二阶段全面开发计划所需的所有性质。第二阶段将包括符合标准的化合物进展到多种疼痛模型的动物疗效测试、大鼠口服剂量的PK研究和毒性测试。 公共卫生相关性： 这项研究的总体目标是确定和开发一种治疗慢性疼痛的新药产品，即TRPA1受体-通道的功能性拮抗剂。目前的治疗方法不足以满足患者的需求，并呈现出显著的安全性、有效性、耐受性和成瘾问题，这些问题往往限制了使用。TRPA1受体/通道在感觉神经中发挥着高度特异性的功能，这些感觉神经在炎症和神经损伤时传递疼痛和痛敏的感觉。由于TRPA1是感觉性伤害性感受器中最重要的疼痛信号整合因子之一，靶向TRPA1是在神经处理的第一阶段阻断伤害性信号的合乎逻辑的方法。TRPA1拮抗剂将作为外周作用的止痛剂发挥作用，因此被设计为没有成瘾和滥用潜力。阿尔格米迪克斯采用了一种创新的理性药理学方法，该方法已被证明能够识别多种新的化学支架，其效力相当于已建立的TRPA1配体。阿尔格米迪克斯使用动力学选择性图谱方法来表征药物作用，这导致了TRPA1的新的药理类别的识别。我们的方法可以识别TRPA1的经典拮抗剂、脱敏激动剂、反向激动剂和变构调节剂。

DESCRIPTION (provided by applicant): Title: Analgesics Targeting TRPA1 for Treatment of Chronic Pain Abstract An effective treatment for chronic pain that is devoid of both addictive potential and abuse liability is a major unmet need in medicine today. These limitations drive the need for novel treatment options based on new molecular mechanisms. Our goal is to identify and develop a novel, first-in-class therapeutic small molecule compound which is a functional antagonist of TRPA1 (Transient Receptor Potential, Subfamily A, member 1) for the treatment of chronic pain. TRPA1-receptor/channels play a highly specific function in sensory nerves that transmit the sensations of pain and hyperalgesia in response to inflammation as well as nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors, targeting TRPA1 is a logical approach to block nociceptive signals at the first stage of neural processing. A TRPA1 antagonist will function as a peripherally acting analgesic and is thus designed to be without addictive and abuse potential. Algomedix employs an innovative rational pharmacology approach which has proven capable of identification of multiple new chemical scaffolds with potency equivalent to established TRPA1 ligands. Algomedix employs a kinetic selectivity profiling approach to characterize drug action which has resulted in identification of new pharmacologic classes for TRPA1. Our approach can identify TRPA1 ligands which are classical antagonists, desensitizing agonists, inverse agonists and allosteric modulators. The aims are: AIM 1 will be to synthesize a group of 30 novel, patentable structural analogs based upon 3 newly discovered TRPA1 ligand active scaffolds. We will initiate medicinal chemistry efforts for enhancing lead potency, selectivity optimization, and to establish structure activity relationship (SAR) analysis. AIM 2 will be to define the potency, pharmacological activity in human and rat TRPA1, kinetics of activation and/or densensitization for novel compounds. AIM 3 will be to define the pharmacological selectivity using a panel of related TRP channels using TRPV1, TRPV3 and TRPM8: AIM 4 wil be to pharmacological Characterize Activity Using Dorsal Root Ganglion (DRG) cells: Kinetics, Homologous TRPA1 Desensitization and Cross- Desensitization with TRPV1. The target cell for TRPA1 antagonist activity is the sensory neuron. We will use the short term culture of dispersed DRG neurons to examine drug effects on native TRPA1 channels within sensory neurons in order to confirm physiological relevance. The final Phase 1 milestone is to deliver an advanced lead molecule and backup compounds that have all properties necessary for nomination to a full development program in Phase 2. Phase 2 will consist of progressing compounds meeting criteria into animal efficacy testing in multiple pain models, PK studies in rat using oral dosing, and toxicity testing. PUBLIC HEALTH RELEVANCE: NARRATIVE The overall objective of this research is to identify and develop a novel drug product for the treatment of chronic pain that is a functional antagonist of TRPA1 receptor-channel. Current therapeutics are inadequate in addressing patient needs and present significant safety, efficacy, tolerability and addiction concerns that often limit use. TRPA1-receptor/channels play a highly specific function in sensory nerves that transmit the sensations of pain and hyperalgesia in response to inflammation as well as nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors, targeting TRPA1 is a logical approach to block nociceptive signals at the first stage of neural processing. A TRPA1 antagonist will function as a peripherally acting analgesic and is thus designed to be without addictive and abuse potential. Algomedix employs an innovative rational pharmacology approach which has proven capable of identification of multiple new chemical scaffolds with potency equivalent to established TRPA1 ligands. Algomedix employs a kinetic selectivity profiling approach to characterize drug action which has resulted in identification of new pharmacologic classes for TRPA1. Our approach can identify TRPA1 ligands which are classical antagonists, desensitizing agonists, inverse agonists and allosteric modulators.