Completion of IND-package for a novel, non-narcotic painkiller

项目摘要 阿片类药物，如吗啡和氢可酮，通常是治疗中度糖尿病最有效的治疗药物 到剧烈的疼痛。然而，它们的使用受到严重副作用的限制-耐受性、便秘、呼吸道 抑郁、身体依赖和高成瘾潜力。临床疼痛的频率，加上 缺乏替代治疗选择导致了以处方阿片类药物滥用为中心的国家健康危机。 替代止痛药具有传统阿片类药物的止痛效力，但没有麻醉副作用 都是迫在眉睫的需要。该项目的目标是开发和商业化一种替代 副作用减少且没有常见成瘾特性的传统阿片类镇痛剂 阿片类药物激动剂。我们的先导分子Blue181是一种高度选择性的中枢神经系统靶标激动剂 是一种有效的止痛药，没有明显的成瘾潜力、耐受性或身体依赖性。我们开始了 Blue181的临床前开发使用联邦和私人资金的组合来扩大和开发 一种产生大量Blue181的工业合成过程，并表明Blue181不会 产生呼吸抑制，减少胃肠道通过，在治疗范围内抑制HERG，或遗传 毒性。我们还对Blue181的药代动力学有了初步的了解。我们现在就会 完成所有剩余的启用IND的研究，目标是Blue181的IV术后疼痛的初步迹象。 我们将继续努力开发符合FDA标准的Blue181制备工艺 千克的规模，将服从稍后的cGMP合成，并准备一个CMC包，以供IND备案。 我们还将进行研究，以进一步描述Blue181的PK和代谢谱，并确定NO- 毒性物种的可观察不良反应水平(NOAEL)。最后，我们将完成安全药理学 对两个物种的研究(肺毒性和心脏毒性)和GLP毒性。在项目期结束时， Blue181将是IND就绪的资产，可以进入第一阶段的人体试验。

Project Summary Opioids like morphine and hydrocodone are generally the most effective therapeutics for treatment of moderate to severe pain. However, their use is limited by serious side effects - tolerance, constipation, respiratory depression, physical dependence and high addictive potential. The frequency of clinical pain, coupled with a lack of alternative therapeutic options has led to a national health crisis centered on prescription opioid abuse. Alternative pain relievers with the analgesic potency of conventional opioids, but devoid of narcotic side effects are an immediate need. The goal of this project is to develop and commercialize an alternative to conventional opioid analgesics with reduced side effects and without the addictive properties common to mu-opioid agonists. Our lead molecule, Blue181 is a highly selective agonist for a novel CNS target that is a potent analgesic without apparent addictive potential, tolerance, or physical dependence. We started the pre-clinical development of Blue181 using a combination of federal and private funds to scale up and develop an industrial synthetic process for generating large amounts of Blue181 and shown that Blue181 does not produce respiratory depression, reduction of GI transit, inhibition of hERG in the therapeutic range, or genetic toxicity. We also have a preliminary understanding of the pharmacokinetic profile of Blue181. We will now finish all the remaining IND-enabling studies targeting an initial indication of IV postoperative pain for Blue181. We will continue our efforts on developing an FDA-compliant process for preparation of Blue181 in the kilogram scale that would be amenable for later cGMP synthesis and prepare a CMC package for IND filing. We will also perform studies to further delineate the PK and metabolic profile of Blue181 and determine the no- observable-adverse-effects-level (NOAEL) in the toxicity species. Finally, we will finish safety pharmacology studies (pulmonary toxicity and cardiotoxicity) and GLP toxicity in two species. At the end of the project period, Blue181 will be an IND-ready asset and can be advanced into Phase 1 human trials.