Arylepoxamides: A new class of potent, safer analgesics

芳基环酰胺：一类新型强效、更安全的镇痛药

• 批准号: 10491268
• 负责人: Jeffrey Reich
• 金额: $ 462.8万
• 依托单位: SPARIAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491268
• 关键词: Absence of pain sensation; Address; Analgesics; Behavior; Biological Assay; Biological Availability; Brain; Categories; Cessation of life; Chronic; Development; Dose; Drug Prescriptions; Epidemic; Formulation; Goals; Growth; Habits; Health Hazards; Health Personnel; Inflammatory; Laboratories; Mediating; Morphine; Neuropathy; Opioid; Opioid Receptor; Oral; Outpatients; Pain; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Physical Dependence; Prodrugs; Reporting; Rewards; Risk; Safety; Series; Site; Toxicology; Ventilatory Depression; Weaning; Withdrawal; addiction; antagonist; base; clinical candidate; conditioned place preference; design; fighting; improved; novel; opioid epidemic; opioid exposure; opioid sparing; opioid therapy; opioid use; phase 1 study; phase I trial; prescription opioid; prescription opioid misuse; receptor; respiratory; side effect

The expansion of opioid prescribing in recent years to better treat pain has markedly increased their usage and availability and fueled an epidemic of abuse. Estimates of up to 80% of addicts reported initiating their habit through prescriptions drugs. Decreasing opioid prescriptions would lower opioid exposure with fewer people receiving the drugs and less drug available for diversion. We have identified a novel target in brain distinct from any of the traditional opioid receptors capable of mediating potent analgesia without the reward behavior and side-effects seen with traditional opioids. We have targeted this site with a series of arylepoxamides and have identified a clinical candidate (MP1000) and backup compound. MP1000 is a potent analgesic in a range of thermal, inflammatory and neuropathic analgesic assays. It fails to show reward behavior and does not produce respiratory depression at doses 5-fold greater than its analgesic ED50. Chronic administration does not produce physical dependence or withdrawal when challenged with an antagonist. It shows no cross tolerance to morphine and can be co- administered to subjects already on opioids for pain to lower their opioid usage (i.e. ‘opioid sparing), facilitating the eventual discontinuation of the opioid. Preliminary safety and toxicology studies are encouraging, and, based upon these results we are proposing to carry out IND- enabling studies and a Phase 1 clinical trial.

近年来，阿片类药物处方的扩大，以更好地治疗疼痛， 他们的使用和可用性，并助长了滥用的流行。估计高达80%的瘾君子 报告说他们是通过处方药开始吸毒的。减少阿片类药物处方将 阿片类药物暴露减少，接受药物的人数减少， 转移注意力我们已经确定了一个新的目标，在大脑中不同于任何传统的阿片类药物 能够介导有效镇痛而无奖赏行为和副作用的受体 与传统的阿片类药物。我们已经用一系列的芳基环氧酰胺瞄准了这个地方， 已经确定了临床候选化合物（MP 1000）和备用化合物。MP 1000是一种有效的 在一系列热、炎性和神经性镇痛测定中的镇痛作用。它没有显示 奖励行为，并不产生呼吸抑制的剂量5倍以上，其 镇痛剂ED 50。长期给药不会产生身体依赖或戒断 当被对手挑战时。它对吗啡无交叉耐受性，可与吗啡联合使用。 向已经服用阿片样物质的受试者施用用于疼痛的药物以降低他们的阿片样物质使用（即“阿片样物质 节省），促进阿片类药物的最终停用。初步安全性和毒理学 研究是令人鼓舞的，基于这些结果，我们建议进行IND- 启动研究和1期临床试验。