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， 导致每年超过5000亿美元的经济负担和超过4.7万人死于阿片类药物 服药过量。超过80%的OUD病例是从使用处方阿片类止痛药开始的，这是 目前是治疗剧烈疼痛的最有效(通常也是唯一可用的)选择。海流 止痛药靶向-阿片受体(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。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飙升的关键原因。新一代汽车的发展 安全有效的止痛药，减少成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)作为一种机制来发展 与阿片受体相关的无成瘾潜力的止痛药以及中枢活性止痛药 CB1激动剂。我们提出了一种以CB1的正位位为靶点的比对方法，以获得效力和 药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，弱脑 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、CYP倾向和 口述活动，我们将寻求通过这个R34提供的U19机制来实现这个目标。ADME和PK 通过R34获得的导线的微调将是U19开发阶段的一部分。 对于R34规划拨款，我们召集了一个多学科团队，目的是测试 对位疗法可以在疼痛和高度受限的外周动物模型中产生有效的化合物 活性，同时对CB1受体表现出选择性。 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.