Synthesis of peripherally active CB1 agonists as analgesics

作为镇痛药的外周活性 CB1 激动剂的合成

基本信息

批准号：
10398527
负责人：
Ron Dror
金额：
$ 103.34万
依托单位：
ST. LOUIS COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-29 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398527
关键词：
Absence of pain sensation Adenosine Adverse effects Afferent Neurons Affinity Agonist Americas Analgesics Animal Model Animals Applications Grants Behavioral Behavioral Assay Binding Binding Proteins Binding Sites Biological Assay Brain CNR1 gene CNR2 gene Cannabinoids Cell Line Cessation of life Characteristics Charge Chemicals Chemistry Chronic Clinical Trials Cryoelectron Microscopy Dependence Development Dopamine Dose Dose-Limiting Drug Kinetics Epidemic Exhibits FDA approved Feeds Fentanyl Funding G-Protein-Coupled Receptors Generations Goals Grant Guanidines Head Health In Vitro Lead Ligands Literature Longevity Mediating Metabolic Opioid Opioid Analgesics Opioid Receptor Oral Outcome Pain Pain Disorder Pain management Patients Penetration Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Plasma Population Property Reporting Resolution Site Sodium Structure Testing Therapeutic Time Ventilatory Depression War Water addiction analog base cannabinoid receptor chronic pain efficacy evaluation endogenous cannabinoid system in vivo lead candidate motivated behavior mu opioid receptors multidisciplinary novel opioid epidemic opioid overdose opioid use disorder pain model prescription opioid prescription opioid misuse public health relevance receptor side effect socioeconomics sodium ion therapeutic target therapeutically effective

项目摘要

ABSTRACT Opioid use disorders (OUD) are responsible for a major health and socioeconomic crisis in the US, resulting in more than $500B burden on the economy and more than 47,000 deaths a year due to opioid overdose. More than 80% of OUD cases started from the use of prescription opioid painkillers, which is currently the most effective (and often the only available) option for treatment of severe pain. The current analgesics target ?-Opioid receptor (MOR), which mediates not only analgesia but also dependence, addiction leading to OUD, as well as respiratory depression and death. Diversion and misuse of prescription opioid drugs in US is the key reason for the skyrocketing opioid epidemic. Development of a new generation of safe and effective analgesics with diminished addiction and abuse potential is desperately needed. We propose to target peripheral cannabinioid receptor subtype 1 (CB1) as a mechanism to develop pain relievers devoid of the addiction potential associated with opioid receptors as well as centrally active CB1 agonists. We propose a bitopic approach targeting the orthosteric site of CB1 to achieve potency and efficacy and allosteric sodium binding pocket to achieve peripheral over central activity in vivo. Our long term goal is to develop an orally active CB1 selective agonist with nM potency, poor brain penetration with optimal drug like properties like protein binding, metabolic stability, no hERG, CYP liability and oral activity, a goal we will seek to achieve through the U19 mechanism this R34 feeds into. ADME and PK fine tuning on leads obtained through R34 will be a part of the U19 phase of development. For this R34 planning grant we bring together a multidisciplinary team with the aim to test if the bitopic approach can lead to compounds with efficacy in animal models of pain and highly restricted peripheral activity while showing selectivity for CB1 receptors. Our optimal compound to be synthesized through this R34 phase will be have the following characteristics: 1) In vitro profile: CB1-agonist with ≤50 nM potency and 100 fold selectivity over other >350 other targets. 2) DMPK profile: Protein binding<5% free at 10 µM, metabolic stability>2h, hERG>10 µM, CYP inhibition/activation <20-30% at 10µM and brain:plasma <0.03. 3) In vivo profile: IP/Oral CB1 mediated analgesic, potency ED50≤5-10 mg/mg with >2.5h analgesic time course and lacking central side-effects like abuse potential and other liabilities upto 15xED50 doses.

抽象的阿片类药物使用障碍 (OUD) 是造成美国重大健康和社会经济危机的原因，每年因阿片类药物过量造成超过 500B 美元的经济负担和超过 47,000 人死亡。超过 80% 的 OUD 病例是从使用处方阿片类止痛药开始的，这是目前最常见的治疗严重疼痛的有效（通常是唯一可用）选择目前的镇痛药目标是 β-阿片类药物。受体（MOR），不仅介导镇痛，还介导导致 OUD 的依赖、成瘾以及在美国，处方阿片类药物的转移和滥用是导致呼吸抑制和死亡的主要原因。急剧上升的阿片类药物流行病。开发新一代安全有效的镇痛药。迫切需要减少成瘾和滥用的可能性。我们建议将外周大麻素受体亚型 1 (CB1) 作为产生疼痛的机制缓解剂缺乏与阿片受体以及中枢活性 CB1 相关的成瘾潜力我们提出了一种针对 CB1 正构位点的双位方法，以实现效力和功效。和变构钠结合袋以实现体内外周活性高于中枢活性。我们的长期目标是开发一种口服活性的 CB1 选择性激动剂，其效力为 nM，但脑渗透性较差具有最佳的药物特性，如蛋白质结合、代谢稳定性、无 hERG、CYP 责任和口服活性，我们将寻求通过 U19 机制来实现这个 R34 的 ADME 和 PK 微调。通过 R34 获得的线索将成为 U19 开发阶段的一部分。对于这项 R34 规划拨款，我们召集了一个多学科团队，旨在测试双主题是否该方法可以产生对疼痛和高度受限的外周活动动物模型有效的化合物同时表现出对 CB1 受体的选择性。我们通过该 R34 相合成的最佳化合物将具有以下特征： 1) 体外概况：CB1 激动剂的效力≤50 nM，选择性比其他 >350 个其他靶标高 100 倍。 2) DMPK 概况：10 µM 时蛋白质结合<5%，代谢稳定性>2 小时，hERG>10 µM，CYP 10μM 时抑制/激活 <20-30%，脑：血浆 <0.03。 3) 体内概况：IP/口服CB1介导的镇痛，效力ED50≤5-10 mg/mg，镇痛时间>2.5h 疗程，并且缺乏中心副作用，如滥用潜力和其他高达 15xED50 剂量的责任。