Arylepoxamides: A new class of potent, safer analgesics

近年来，为更好地治疗疼痛而扩大的阿片类药物处方明显增加 它们的使用和可获得性，并助长了滥用的流行。据估计，高达80%的吸毒者 据报道，他们通过处方药物养成了自己的习惯。减少阿片类药物处方将 较低的阿片类药物暴露，接受药物治疗的人较少，可用于治疗的药物较少 转移视线。我们在大脑中发现了一个新的靶点，与任何传统的阿片类药物截然不同 无奖赏行为和副作用的受体能够介导有效的镇痛作用 与传统的阿片类药物有关。我们已经用一系列芳香来泊沙胺和 已经确定了一种临床候选药物(MP1000)和备用化合物。MP1000是一款强大的 一系列热性、炎性和神经性止痛试验中的止痛药。它没有显示出 奖励行为，并且不会产生呼吸抑制，剂量是其5倍 止痛药ED50。长期服药不会导致身体依赖或戒断 当受到对手的挑战时。它对吗啡没有交叉耐受性，可以联合 给已经服用阿片类止痛药的受试者减少阿片类药物的使用(即阿片类药物 节约)，为阿片类药物的最终停用提供便利。初步安全性和毒理学 研究令人鼓舞，根据这些结果，我们建议开展IND-- 使能研究和一期临床试验。

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.