Development of an oral analgesic with reduced liabilities

开发可减少负债的口服镇痛药

• 批准号: 10604391
• 负责人: Donald R Gehlert
• 金额: $ 148.89万
• 依托单位: EPIODYNE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604391
• 关键词: Agonist; Analgesics; Behavioral; Biological Assay; Biological Availability; Brain; Buprenorphine; Canis familiaris; Caring; Cessation of life; Chemicals; Chronic; Classification; Clinical; Clinical Trials; Dangerousness; Data; Development; Dose; Dose Limiting; Evaluation; Evolution; Exhibits; Generations; Goals; Government; Grant; Human; In Vitro; Libraries; Ligands; Medical; Metabolism; Molecular; Opioid; Opioid Receptor; Opioid agonist; Oral; Overdose; Oxycodone; Pain; Pain management; Patients; Persons; Pharmaceutical Preparations; Phase; Physiology; Property; Rattus; Research; Risk; Rodent; Safety; Series; Serious Adverse Event; Testing; Therapeutic; Toxicology; Tramadol; Treatment Efficacy; Ventilatory Depression; Work; abuse liability; addiction; addiction liability; carcinogenicity; comparative efficacy; design; drug development; insight; meetings; mu opioid receptors; novel; pre-clinical; prescription opioid; public health relevance; receptor; respiratory; risk mitigation; scaffold; single molecule; small molecule; stem; therapeutic opioid

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.

抽象的 具有较高受体水平活性的口服MU-阿片受体（MOR）激动剂仍然是疼痛的主要治疗方法 （在美国，每年约有7.02亿口腔阿片类药物疼痛处方）。但是，这些化合物 是添加剂，具有危险的呼吸抑郁水平。被归类为“弱”的动力学家 像丁丙诺啡和曲马多一样，减少了这些严重的不良事件（SAE），但它们保留了许多责任 防止它们取代更多的添加剂和危险化合物，例如羟考酮。多达25％的患者 接受阿片类药物处方有成瘾的风险或需要医疗服务的SAE。阻止这种潮流 需要一个更好的部分动力学家。 Epiodyne使用新型的MOR-配体支架，开发了一系列潜在的口服生物利用 药物状的小分子。从这个系列中，我们选择了我们的开发候选EPD2520； EPD2520是a 偏向局部激动剂，表现出与非致命剂量的羟考酮相当的镇痛效率，几乎没有 没有呼吸道抑郁症，而大鼠的虐待责任显然比丁丙诺啡少。除了 有希望的行为特征，EPD2520似乎也适用于慢性给药。安全问题 在体外筛查中未检测到包括受体选择性，致癌性，QT延长，代谢 ID和CYP抑制测定。在这个项目中，我们将1）提前EPD2520启用研究并提交 印第安和2）研究新型的配体 - 受体 - 生理学相互作用，以设计第二代化合物 建立在效率的基础上，诸如属性的药物和EPD2520的负债降低。我们预计EPD2520将会 成为高效的镇痛药，减少呼吸和成瘾责任。