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抑郁症的最有效的治疗剂。 到剧烈疼痛。然而，它们的使用受到严重副作用的限制-耐受性，便秘，呼吸道感染， 抑郁、身体依赖和高成瘾性。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全国性健康危机。 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 是一个迫切的需要。该项目的目标是开发一种替代品， 传统的阿片类镇痛药，副作用减少，没有常见的成瘾性， 到μ阿片激动剂我们的先导分子Blue 181是一种新型CNS靶点的高选择性激动剂， 是一种有效的止痛药，没有明显的成瘾性、耐受性或身体依赖性。我们开始 利用联邦和私人基金的组合进行Blue 181的临床前开发，以扩大和开发 一种用于产生大量Blue 181的工业合成方法，并显示Blue 181不 在治疗范围内产生呼吸抑制、GI转运减少、hERG抑制，或遗传性 毒性我们也初步了解了Blue 181的药代动力学特征。我们现在将 完成所有剩余的IND使能研究，目标是Blue 181的IV术后疼痛的初始适应症。 我们将继续努力开发符合FDA要求的制备Blue 181的工艺， 公斤规模，这将适合于以后的cGMP合成，并准备一个CMC包IND申请。 我们还将进行研究，以进一步描述Blue 181的PK和代谢特征，并确定其无毒性。 毒性种属的可观察不良作用水平（NOAEL）。最后完成安全药理学 研究（肺毒性和心脏毒性）和两个种属的GLP毒性。在项目期结束时， Blue 181将成为一种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.