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

基本信息

批准号：
10450923
负责人：
Jeffrey Reich
金额：
$ 459.52万
依托单位：
SPARIAN BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
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

项目摘要

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，为了更好地治疗疼痛，阿片类药物处方的扩大显着增加据估计，多达 80% 的成瘾者普遍滥用这些药物。据报道，通过处方药养成习惯会减少阿片类药物的处方。由于接受药物的人数较少且可用于治疗的药物较少，因此阿片类药物的暴露量较低我们已经在大脑中发现了一个不同于任何传统阿片类药物的新靶点。能够介导有效镇痛而没有奖励行为和副作用的受体我们用一系列芳基环酰胺和传统阿片类药物来瞄准这个部位。已经确定了一种临床候选药物 (MP1000)，并且 MP1000 是一种有效的备用化合物。在一系列热镇痛、炎症镇痛和神经病理性镇痛试验中未能显示出镇痛作用。奖励行为，并且在剂量大 5 倍时不会产生呼吸抑制镇痛ED50。长期给药不会产生身体依赖性或戒断。当用拮抗剂攻击时，它对吗啡没有交叉耐受性，并且可以共同作用。对已经服用阿片类药物的受试者进行治疗以减少阿片类药物的使用（即“阿片类药物”）保留），促进阿片类药物的初步安全性和毒理学的最终停用。研究令人鼓舞，根据这些结果，我们建议开展 IND- 开展研究和一期临床试验。