Development of a non-addictive analgesic targeting opioid receptor heteromers.

开发一种针对阿片受体异聚物的非成瘾性镇痛药。

• 批准号: 9321201
• 负责人: Ajay S Yekkirala
• 金额: $ 65.57万
• 依托单位: BLUE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321201
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Agonist; Analgesics; Animals; Binding; Biological; Biological Assay; Caring; Charcoal; Chemicals; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Constipation; Coupled; Data; Dependence; Development; Dose; Feasibility Studies; Formulation; Frequencies; Future; Goals; Health; Human; Hydrocodone; In Vitro; Intravenous; Lead; Licensing; Ligands; Medical; Methods; Minnesota; Morphine; Mus; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Outcome; Overdose; Oxycodone; Pain; Pain management; Patients; Pharmacology; Phase; Physical Dependence; Plasma; Postoperative Pain; Pre-Clinical Model; Preparation; Process; Property; Rattus; Research; Respiration; Respiratory System; Rodent; Rodent Model; Safety; Series; Small Business Innovation Research Grant; Stomach; Synthesis Chemistry; Testing; Therapeutic; Toxicology; Treatment Efficacy; United States; Universities; Ventilatory Depression; Whole Body Plethysmography; Work; analytical method; base; chronic pain; commercialization; cost; drug seeking behavior; effective therapy; in vivo; kappa opioid receptors; metabolic profile; method development; novel; opioid abuse; opioid use; phase 3 study; preclinical development; prescription opioid; prescription opioid abuse; public health relevance; scale up; screening; small molecule; standard of care

 DESCRIPTION (provided by applicant): Opioids like morphine, hydrocodone and oxycodone are generally the most effective therapeutic approach for treatment of moderate to severe pain. However, their use is limited by serious side effects, including rapid tolerance, constipation, respiratory depression, 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 without their side effects and abuse potential are needed. 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. In our SBIR Phase I equivalent studies, N-naphthoyl-β- naltrexamine (NNTA) was shown to be orally and intravenously (i.v.) active and demonstrated potent analgesia without apparent addictive potential as indicated by lack of significant intrathecal tolerance, physical dependence, and abuse potential in standard rodent assays. We further showed that NNTA is highly selective for a novel biological target, the mu-kappa opioid heterodimer. We will now move NNTA through a series of IND-enabling studies targeting an initial indication of i.v. postoperative pain. We will first develop an FDA- compliant process for preparation of NNTA hydrochloride based on a previously demonstrated robust, three- step synthetic strategy. Upon completion of this milestone, we will obtain at least 30g of 95% NNTA using a scalable synthetic process. We will next perform studies to further differentiate NNTA from conventional opioids by identifying its potential to produce constipation and respiratory depression. Because NNTA targets the mu-kappa receptor and is not a mu agonist, we hypothesize that these side effects will be absent or greatly reduced compared to the effects produced by morphine. To explore its propensity to produce constipation, the effects of i.v. NNTA on gastric transit will be tested using the charcoal meal method and compared to the effects of i.v. morphine. We will then compare the effects of NNTA and morphine on respiration by using whole body plethysmography. In these studies we aim to show that NNTA produces less respiratory depression and less constipation than morphine at the ED50 of both compounds. Next, utilizing a CRO, we will advance NNTA through in vitro ADME, bacterial mutagenicity, and hERG assays. Additionally we will develop and validate bioanalytical methods exploring plasma PK properties in rodent and non-rodent species and validate analytical methods for compound formulation and vehicle stability. By advancing NNTA through these IND-enabling milestones, and further differentiating its side effect profile, this SBIR Phase II project prepares NNTA for planned SBIR Phase III studies that will advance it into Phase 1 human trials.

 描述（由申请人提供）：阿片类药物如吗啡、氢可酮和羟考酮通常是治疗中度至重度疼痛的最有效治疗方法。然而，它们的使用受到严重副作用的限制，包括快速耐受性，便秘，呼吸抑制和高成瘾性。临床疼痛的频率，加上缺乏替代治疗方案，导致了以处方阿片类药物滥用为中心的全国性健康危机。需要具有常规阿片类药物镇痛效力但没有其副作用和滥用可能性的替代止痛药。这个项目的目标是 开发和商业化常规阿片类镇痛剂的替代品，其副作用减少，并且没有μ-阿片类激动剂常见的成瘾特性。在我们的SBIR I期等效研究中，N-萘甲酰基-β-纳洛酮胺（NNTA）被证明是口服和静脉内（i. v.）在标准啮齿类动物试验中缺乏显著的鞘内耐受性、身体依赖性和滥用潜力表明，活性和表现出的有效镇痛作用没有明显的成瘾潜力。我们进一步表明，NNTA是一种新的生物靶点，mu-kappa阿片异源二聚体的高度选择性。我们现在将通过一系列IND使能研究来推动NNTA，这些研究的目标是术后疼痛的初始适应症。我们将首先开发一种符合FDA要求的工艺，用于基于先前证明的稳健的三步合成策略制备NNTA盐酸盐。完成这一里程碑后，我们将使用可扩展的合成工艺获得至少30克95%的NNTA。我们接下来将进行研究，通过确定其产生便秘和呼吸抑制的潜力，进一步将NNTA与传统阿片类药物区分开来。由于NNTA靶向mu-kappa受体，而不是mu激动剂，因此我们假设这些副作用与吗啡产生的作用相比将不存在或大大减少。为了探索其产生便秘的倾向，将使用活性炭测试静脉注射NNTA对胃转运的影响。 餐法，并与静脉注射吗啡的效果进行比较。然后，我们将使用全身体积描记法比较NNTA和吗啡对呼吸的影响。在这些研究中，我们的目的是表明，在两种化合物的ED 50下，NNTA产生的呼吸抑制和便秘比吗啡少。接下来，利用CRO，我们将通过体外ADME、细菌致突变性和hERG试验推进NNTA。此外，我们将开发和验证探索啮齿动物和非啮齿动物种属中血浆PK特性的生物分析方法，并验证化合物制剂和溶媒稳定性的分析方法。通过推进NNTA通过这些IND使能里程碑，并进一步区分其副作用特征，该SBIR II期项目为计划的SBIR III期研究准备NNTA，将其推进到1期人体试验。