Development of Adrb3 Antagonists for the Treatment of Pain

项目总结 慢性原发疼痛状况(CPPC)影响着1亿多人，但仍然没有得到有效的治疗 传统药物疗法，如阿片类药物，疗效较差，有不良的中枢副作用。这个 这项提案的目标是为CPPC患者开发更安全、更有效的止痛药。具体来说，我们将 开发有效的、选择性的、外周受限的肾上腺素能受体β-3(ADRB3)拮抗剂。ADRB3为 一种由儿茶酚胺激活的G蛋白偶联受体。在临床研究中，我们确定患者 患有CPPC的患者，如纤维肌痛、下腰痛和肠易激综合征，都会增加 儿茶酚胺与降低的儿茶酚-O-甲基转移酶(COMT；一种代谢酶 儿茶酚胺)。与临床发现一致，我们的实验室已经表明，遗传或药物抑制 啮齿动物COMT通过ADRB3及其下游的儿茶酚胺激活在多个身体部位产生疼痛 促进炎症和增加的效应物(如细胞因子和p38丝裂原激活的蛋白激酶) 痛觉伤害感受器的活动。因此，ADRB3是治疗慢性粒细胞白血病的一个新的和有吸引力的靶点。 原发疼痛。然而，只有为数不多的ADRB3拮抗剂工具化合物存在，甚至是最有效和最有选择性的 我们的初步药代动力学研究表明，拮抗剂L-748,336具有较差的代谢特性。 此外，还需要进一步的工作来确定ADRB3拮抗剂逆转慢性原发性疼痛的能力。 因此，我们的目标是为ADRB3拮抗剂开发一个药物发现平台。为了实现这一目标，我们建议 1)在已有的L-748,337芳氧基丙醇胺支架的基础上，开发新的ADRB3拮抗剂 提高药效、类药物性质和外周选择性，2)测试L-748,337和新生的能力 合成ADRB3拮抗剂逆转COMT依赖的疼痛和伤害性感受器活性 影响(例如，成瘾、心脏、尿路)，以及3)发展一支在疼痛生物学方面具有专业知识的多学科团队， 药物化学、药物开发、调节和商业化以及临床疼痛 管理、临床试验和患者倡导，以使我们的类铅化合物成功应用于U19 治疗药物发现平台。这些研究的成功完成将导致新的 外周受限止痛药，适合进入人体试验，具有潜在的 对数百万患有慢性原发疼痛的人的生活质量产生积极影响。

PROJECT SUMMARY Chronic primary pain conditions (CPPCs) affect over 100 million people, yet remain ineffectively treated by conventional pharmacotherapies, such as opioids, that have poor efficacy and adverse central side effects. The goal of this proposal is to develop safer, more effective analgesics for patients with CPPCs. Specifically, we will develop potent, selective, peripherally-restricted antagonists of the adrenergic receptor beta-3 (Adrb3). Adrb3 is a G protein-coupled receptor that is activated by catecholamines. In clinical studies, we determined that patients with CPPCs such as fibromyalgia, low back pain, and irritable bowel syndrome have increased levels of catecholamines alongside reduced levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical findings, our lab has shown that genetic or pharmacologic inhibition of COMT in rodents produces pain at multiple body sites via catecholamine activation of Adrb3 and its downstream effectors (eg, cytokines and p38 mitogen activated protein kinase) that promote inflammation and increase activity of pain-sensing nociceptors. Thus, Adrb3 is a novel and attractive target for the treatment of chronic primary pain. Yet, only a few antagonist tool compounds for Adrb3 exist, and even the most potent and selective antagonist L-748,336 has poor metabolic properties as identified by our preliminary pharmacokinetic studies. Further, additional work is needed to determine the ability of Adrb3 antagonists to reverse chronic primary pain. Thus, our objective is to develop a drug discovery platform for Adrb3 antagonists. To accomplish this, we propose to 1) develop novel Adrb3 antagonists based on the existing aryloxy propanolamine scaffold in L-748,337 with improved potency, drug-like properties, and peripheral selectivity, 2) test the ability of L-748,337 and newly synthesized Adrb3 antagonists to reverse COMT-dependent pain and nociceptor activity in the absence of side- effects (eg, addiction, cardiac, urinary), and 3) develop a multidisciplinary team with expertise in pain biology, medicinal chemistry, and drug development, regulation, and commercialization as well as clinical pain management, clinical trials, and patient advocacy to progress our lead-like compounds to a successful U19 therapeutics discovery platform. Successful completion of these studies will lead to the development of new peripherally-restricted analgesics that are suitable for advancement into human trials with the potential to have a positive impact on the quality of life for the millions who suffer from chronic primary pain.