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

• 批准号: 10891251
• 负责人: Ron Dror
• 金额: $ 53.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10891251
• 关键词: Synthesis; peripherally; active; CB1; agonists

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.

摘要 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， 导致超过5000亿美元的经济负担和超过47，000人死亡，每年由于阿片类药物 服药过量超过80%的OUD病例始于使用处方阿片类止痛药， 目前最有效的（通常是唯一可用的）治疗严重疼痛的选择。当前 镇痛药靶向β-阿片受体（莫尔），其不仅介导镇痛，而且介导依赖、成瘾 导致OUD以及呼吸抑制和死亡。处方阿片类药物的转移和滥用 美国的毒品是阿片类药物流行病飙升的关键原因。发展新一代 迫切需要具有降低的成瘾和滥用可能性的安全和有效的止痛剂。 我们建议靶向外周大麻素受体亚型1（CB 1）作为一种机制， 没有与阿片受体相关的成瘾潜力以及中枢活性的止痛药 CB 1激动剂。我们提出了一种针对CB 1的正构位点的双位方法来实现效力， 有效性和变构钠结合口袋以实现体内外周活性超过中枢活性。 我们的长期目标是开发一种口服活性CB 1选择性激动剂，具有nM效力， 具有最佳药物性质的渗透性，如蛋白质结合、代谢稳定性、无hERG、易变性和 口服活性，我们将寻求通过U19机制实现这一目标R34饲料。ADME和PK 对通过R34获得的引线进行微调将是U19开发阶段的一部分。 对于这项R34规划补助金，我们召集了一个多学科团队，旨在测试 双位方法可以导致化合物在疼痛和高度限制的外周神经损伤的动物模型中具有功效。 活性，同时显示对CB 1受体的选择性。 我们通过R34阶段合成的最佳化合物将具有以下特征： 1)体外特征：CB 1-激动剂具有≤50 nM的效力和超过其他>350种其他靶标的100倍选择性。 2)DMPK谱：10 µM时蛋白结合<5%游离，代谢稳定性> 2 h，hERG>10 µM， 抑制/活化<20-30%（10µM），脑：血浆<0.03。 3)体内特性：IP/口服CB 1介导的镇痛剂，效力ED 50 ≤5-10 mg/mg，镇痛时间> 2.5小时 过程中，没有中央副作用，如滥用的可能性和其他责任高达15 xED 50剂量。