Control of Arthritic Pain by Inhibition of TRPA1 Activity

描述(由申请人提供)：一种安全有效的治疗骨关节炎(OA)的疗法代表着一个主要的未得到满足的医疗需求。在美国，骨性关节炎是导致残疾的主要原因，而疼痛是主要的临床特征。然而，长期使用非类固醇抗炎药(NSAIDs)与潜在威胁生命的胃肠道出血有关，计算估计，美国每年约有10万名患者因NSAID相关的胃肠道并发症住院，美国每年约有16,500名关节炎患者发生与NSAID相关的死亡，导致20亿美元的医疗费用。这项提案的目标是 是开发一种新的治疗方法，基于一种新的分子机制，该机制针对参与关节伤害性信号传递的关键分子。我们建议开发一种新型的、一流的治疗性小分子化合物，它是TRPA1(瞬时受体电位，A亚家族，成员1)的功能拮抗剂，用于治疗骨性关节炎疼痛。TRPA1受体/通道在关节的感觉神经纤维终末上起着高度特异的作用 检测并传递疼痛和痛敏的感觉，以响应炎症和神经损伤。由于TRPA1是关节感觉伤害性感受器中最重要的疼痛信号整合因子之一，TRPA1的拮抗剂将作为一种外周作用的止痛剂发挥作用。我们的创新方法是基于新型治疗药物的开发，这种药物将在神经处理的第一阶段阻断伤害性信号，并且不涉及中枢神经系统的作用。该项目的长期目标是确定口服的TRPA1拮抗剂，这种拮抗剂将阻断关节中存在的、在骨性关节炎中被激活的伤害性传入纤维的兴奋。这种方法是基于遗传和体内药理学证据，即调节TRPA1的活性将具有治疗价值。我们的目标是：目标1将利用一种新的支架，基于新发现的TRPA1配体合成一组75种新颖的结构类似物。将利用合成药物化学和结构指导的药物设计努力来提高铅的效力，并进一步确定结构-活性关系(SAR)。目标2将确定新化合物对人和大鼠TRPA1的效力和药理作用。在AIM 3中，将使用一组相关的Trp通道，包括TRPV1、TRPV3、TRPM8和几个TRPC成员，在Trp超家族成员中定义新型拮抗剂的药理选择性。AIM 4将利用培养的背根节神经元(TRPA1的主要靶细胞)对新药的活性进行药理学表征，AIM 5将对顶级活性化合物进行体外ADME分析，并通过口服剂量确定药代动力学。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。预期的第二阶段计划将包括在多个OA模型中进行动物药效测试，以及使用口服剂量在多个动物物种中进行药代动力学研究，以便能够提交IND。

DESCRIPTION (provided by applicant): A safe and effective therapeutic for treatment of osteoarthritis (OA) represents a major unmet medical need. OA is the leading cause of disability in the US and pain is a predominant clinical feature. However, chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with potentially life-threatening gastrointestinal bleeding and calculations estimate that about 100,000 patients are hospitalized annually for NSAID related GI complications and about 16,500 NSAID-related deaths occur among arthritis patients in the US each year, leading to $2 billion in health care costs. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets a key molecule involved in nociceptive signaling from the joint. We propose to 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 OA pain. TRPA1-receptor/channels serve a highly specific function on sensory nerve fiber endings in the joint that detect and transmit the sensations of pain and hyperalgesia in response to inflammation and nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors in the joint, an antagonist of TRPA1 will function as a peripherally acting analgesic. Our innovative approach is based on development of novel therapeutic agent that will block nociceptive signals at the first stage of neural processing and does not involve CNS action. Algomedix employs a rational pharmacology approach and has already made substantial progress in the identification of novel, small molecule chemical antagonists of TRPA1 The long-term goal of this project is to identify orally available antagonists of TRPA1 that will block the excitation of the nociceptive afferent fibers present in the joint that are activated in OA. This approach is based upon genetic and in vivo pharmacologic evidence that modulation of TRPA1 activity will have therapeutic value. The aims are: AIM 1 will be to synthesize a group of 75 novel, structural analogs based upon newly discovered TRPA1 ligands using a novel scaffold. Synthetic medicinal chemistry and structure guided drug design efforts will be used to enhance lead potency and to further define structure-activity relationships (SAR). AIM 2 will be to define the potency and pharmacological of novel compounds on human and rat TRPA1. In AIM 3, the pharmacological selectivity for novel antagonists will be defined among members of the TRP superfamily using a panel of related TRP channels, including TRPV1, TRPV3, TRPM8 and several TRPC members. AIM 4 will pharmacologically characterize the activity of the new drug using cultured dorsal root ganglion neurons, which are the primary target cell for TRPA1, and AIM 5 will conduct in vitro ADME profiling for the top-ranked active compounds and determine pharmacokinetics using oral dosing. 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. The anticipated Phase 2 program will consist of animal efficacy testing in multiple OA models and conducting pharmacokinetic studies in multiple animal species using oral dosing to enable the filing of an IND.