Development of an oral analgesic with reduced liabilities

摘要 具有高受体活性的口服阿片受体(MOR)激动剂仍然是治疗疼痛的主要药物 (在美国，每年约有7.02亿张口服阿片类止痛药。)然而，这些化合物 会上瘾，并有危险的呼吸抑制程度。被归类为“较弱”的MOR激动剂 像丁丙诺啡和曲马多一样，可以减少这些严重不良事件(SAE)，但它们保留了许多责任， 防止它们取代更容易上瘾和更危险的化合物，如羟考酮。高达25%的患者 接受阿片类药物处方有成瘾或需要医疗护理的SAE的风险。阻挡这股浪潮 需要更好的部分MOR激动剂。 使用一种新的配基支架，Epiodyne已经开发出一系列有效的口服生物利用度 类似毒品的小分子。从本系列中，我们选择了开发候选EPD2520；EPD2520是一个 MOR部分激动剂，显示出与非致死剂量羟考酮相当的止痛效果，几乎没有 没有呼吸抑制，在大鼠身上滥用的可能性明显低于丁丙诺啡。除了 EPD2520有希望的行为特征，似乎也适合慢性给药。安全问题 在体外筛选中未检测到受体选择性、致癌性、QT延长、代谢 ID和CYP抑制试验。在此项目中，我们将1)将EPD2520推进到IND启用研究并提交 Ind.以及2)研究新的配体-受体-生理相互作用，以设计第二代化合物 以EPD2520的功效、类似药物的特性和降低的负债为基础。我们预计EPD2520将 是一种高效的止痛剂，减少了呼吸和成瘾的风险。

Abstract Oral mu-opioid receptor (MOR) agonists with high receptor level activity remain the primary treatment for pain (about 702 million oral opioid pain prescriptions are dispensed per year in the US). However, these compounds are addictive and have dangerous levels of respiratory depression. MOR agonists that are classified as “weaker” like buprenorphine and tramadol reduce these serious adverse events (SAE), but they retain many liabilities that keep them from displacing more addictive and dangerous compounds like oxycodone. Up to 25% of patients receiving opioid prescriptions are at risk of addiction or an SAE that requires medical care. Stemming this tide requires a better partial MOR agonist. Using a novel MOR-ligand scaffold, Epiodyne has developed a promising series of potent orally bioavailable drug-like small molecules. From this series, our development candidate EPD2520 was selected; EPD2520 is a MOR partial agonist, that exhibits analgesic efficacy comparable to non-lethal doses of oxycodone, with little to no respiratory depression, and with apparently less abuse liability in rats than buprenorphine. In addition to a promising behavioral profile, EPD2520 also appears to be suitable for chronic administration. Safety issues were not detected in in-vitro screens including receptor selectivity, carcinogenicity, QT prolongation, metabolism ID and CYP inhibition assays. In this project we will 1) advance EPD2520 to IND enabling studies and file an IND. And 2) investigate novel ligand-receptor-physiology interactions to design 2nd generation compounds that build on the efficacy, drug like properties and reduced liabilities of EPD2520. We anticipate that EPD2520 will be a highly efficacious analgesic with reduced respiratory and addiction liabilities.