Development of Adrb3 Antagonists for the Treatment of Pain

用于治疗疼痛的 Adrb3 拮抗剂的开发

• 批准号: 10730831
• 负责人: Chunyang Jin
• 金额: $ 184.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730831
• 关键词: 3T3-L1 Cells; Adipocytes; Adrenergic Antagonists; Adverse effects; Affect; Analgesics; Antidepressive Agents; Binding; Biological Assay; Biology; Brain; Cardiac; Catechol O-Methyltransferase; Catecholamines; Cell Line; Cells; Central Nervous System; Chronic; Clinical; Clinical Research; Clinical Trials; Communication; Complement; Computer Analysis; Cyclic AMP; Data; Development; Drug Kinetics; Electronics; Enzymes; Event; Fibromyalgia; Funding; G-Protein-Coupled Receptors; Genetic; Genetic Predisposition to Disease; Goals; Healthcare; Homology Modeling; Human; In Vitro; Inflammation; Infrastructure; Irritable Bowel Syndrome; Knock-out; Lead; Life; Low Back Pain; Metabolic; Modeling; Modification; Mus; Neuroglia; Nociceptors; Opioid; Oral; Pain; Pain management; Patient advocacy; Patients; Penetration; Peripheral; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Propanolamines; Property; Quality of life; Receptors, Adrenergic, beta-3; Regulation; Rodent; Series; Site; Solubility; Specificity; Spinal Cord; Syndrome; Temporomandibular Joint Disorders; Testing; Therapeutic; Treatment Protocols; Ventilatory Depression; Work; addiction; addiction liability; analog; antagonist; antinociception; calcium indicator; chronic pain; chronic pain management; clinical pain; clinical translation; commercialization; comorbidity; cytokine; data management; depressive behavior; design; drug development; drug discovery; improved; in vivo; in vivo calcium imaging; meetings; mental state; mouse model; multidisciplinary; novel; p38 Mitogen Activated Protein Kinase; pain behavior; pain model; pharmacologic; pharmacophore; pre-clinical assessment; preclinical study; prevent; radioligand; receptor; relational database; scaffold; side effect; therapeutic development; tool; urinary

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.

项目摘要 慢性初次疼痛状况（CPPC）影响了1亿多人，但仍在不理治疗。 常规的药物疗法，例如阿片类药物，其功效和不良中心副作用。这 该建议的目标是为CPPC患者开发更安全，更有效的镇痛药。具体来说，我们会的 发展肾上腺素能受体β-3（ADRB3）的有效，选择性，外围限制性拮抗剂。 ADRB3是 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 与纤维肌痛，下背痛和肠易激综合征等CPPC的水平增加 儿茶酚胺以及降低的儿茶酚-O-甲基转移酶（COMT；一种代谢的酶 儿茶酚胺）。与临床发现一致，我们的实验室表明，遗传或药理抑制 啮齿动物中的COMT通过Catecholamine激活ADRB3及其下游会产生多个身体部位的疼痛 效应子（例如，细胞因子和p38有丝分裂原激活的蛋白激酶）促进炎症并增加 疼痛感性伤害感受器的活性。因此，ADRB3是一个新颖而有吸引力的慢性治疗目标 初级疼痛。但是，仅存在ADRB3的几种拮抗剂工具化合物，甚至最有效，有选择性 拮抗剂L-748,336的代谢特性较差，如我们的初步药代动力学研究所确定的。 此外，还需要额外的工作来确定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。为此，我们提出 到1）基于现有的L-748,337中现有的芳氧甲氧丙氨酸支架开发新型ADRB3拮抗剂 提高效力，类似药物的特性和外围选择性，2）测试L-748,337和新近的能力 合成的ADRB3拮抗剂在没有侧面 - 效果（例如，成瘾，心脏，尿液）和3）发展具有疼痛生物学专业知识的多学科团队， 药物化学以及药物开发，调节和商业化以及临床疼痛 管理，临床试验和患者倡导我们的类似铅样化合物到成功的U19 Therapeutics Discovery平台。这些研究的成功完成将导致新的发展 外围限制的镇痛药，适合于人类试验，并有可能具有 遭受慢性初次疼痛的数百万痛苦的生活质量产生积极影响。