Synthesis of peripherally active CB1 agonists as analgesics

摘要 阿片类药物使用障碍(OUD)是美国主要的健康和社会经济危机的罪魁祸首，结果 每年因阿片类药物过量造成的经济负担超过5000亿美元，死亡人数超过4.7万人。更多 超过80%的OUD病例是从处方阿片类止痛药的使用开始的，这是目前最多的 治疗剧烈疼痛的有效(通常也是唯一可用的)选择。目前的止痛药靶点是什么？-阿片类药物 受体(MOR)，它不仅介导镇痛，而且还介导依赖，成瘾导致OUD，以及 呼吸抑制和死亡。美国处方阿片类药物的转移和滥用是导致 暴涨的阿片类药物流行。新一代安全有效止痛药的研制 减少上瘾和滥用的可能性是迫切需要的。 我们建议靶向外周大麻素受体亚型1(CB1)作为产生疼痛的机制。 缺乏与阿片受体和中枢活性CB1相关的成瘾潜力的缓释剂 激动剂。我们提出了一种靶向CB1正构位的方法，以达到效力和疗效。 和变构钠结合袋，实现外周高于中枢的体内活性。 我们的长期目标是开发一种口服活性CB1选择性激动剂，具有NM效力，大脑渗透性差 具有最佳的类药物特性，如蛋白质结合、代谢稳定性、无HERG、CYP倾向性和口服活性， 我们将通过R34提供的U19机制来实现这一目标。启用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，目的是测试比特眼 方法可以导致在疼痛和高度限制外周活动的动物模型中具有疗效的化合物 同时表现出对CB1受体的选择性。 我们通过这个R34相合成的最佳化合物将具有以下特征： 1)体外实验：CB1激动剂具有≤50 nm的效力和100倍于其他靶点的选择性。 2)DMPK图谱：蛋白质结合在10微米时游离5%，代谢稳定性和GT；2小时，HERG和GT；10微米，CYP 抑制/激活在10微米时为20-30%，脑：血浆为0.03。 3)体内分布：ip/口服CB1介导的镇痛剂，效价ED50≤5-10 mg/mg，镇痛时间2.5h 疗程和缺乏中心副作用，如滥用的可能性和其他责任高达15×ED50剂量。

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.