Peripheral FAAH as a target for novel analgesics

外周 FAAH 作为新型镇痛药的靶点

• 批准号: 9454448
• 负责人: Daniele Piomelli
• 金额: $ 39.82万
• 依托单位: ANTEANA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454448
• 关键词: Acute Pain; Ames Assay; Analgesics; Animal Model; Biological; Biological Assay; Biological Availability; Biology; Brain; Capital; Chemistry; Clinic; Clinical; Collection; Constipation; Consult; Data; Development; Drug Kinetics; Endocannabinoids; Enzymes; Experimental Models; FAAH inhibitor; Generations; Goals; Human; Industry; Investigational Drugs; Investigational New Drug Application; Investments; Ion Channel; Knowledge; Lead; Link; London; Marijuana; Mediator of activation protein; Medical; Membrane Transport Proteins; Mus; Neuraxis; Neurotransmitters; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Oral; Pain; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Play; Postoperative Pain; Potassium; Privatization; Property; Rattus; Regulation; Regulatory Affairs; Rice; Role; Safety; Scientist; Sedation procedure; Series; Services; Spinal Cord; Stomach; Toxicology; Translating; United States Food and Drug Administration; Work; addiction; anandamide; base; brain cell; circulating biomarkers; clinical development; college; drug metabolism; experience; fatty acid amide hydrolase; general acute pain; genotoxicity; health economics; innovation; novel; novel therapeutics; pain relief; peripheral pain; preclinical development; professor; programs; public health relevance; receptor; research clinical testing; side effect

 DESCRIPTION (provided by applicant): Pain management is a significant unmet medical need. Anandamide is an endocannabinoid mediator that plays important roles in the regulation of pain. Previous work has shown that endocannabinoid receptors located outside the central nervous system (CNS) exert a powerful regulatory control over pain initiation. The biological actions of anandamide are stopped by the enzyme, fatty acid amide hydrolase (FAAH). To explore the role of anandamide in the peripheral regulation of pain, our lab has developed a novel class of FAAH inhibitors that do not enter the CNS. The lead compound in this class, called URB937, exerts profound analgesic effects in animal models, suggesting that peripheral FAAH blockade may offer an innovative approach to pain therapy. Work done during the Phase 1 of the present application has demonstrated that URB937 (a) suppresses postoperative pain in mice more effectively than do currently used analgesics; (b) does not cause side effects typical of those drugs (i.e., sedation, constipation, gastric damage); (c) shows a high degree of target selectivity; (d) has excellent oral bioavailability in rats; and (e) exerts no genotoxic effcts in the Ames' test and does not inhibit the human potassium hERG channel. These results identify URB937 as a suitable candidate for preclinical development in postoperative pain, an extremely common but still underserved pain condition. The objective of present proposal is to complete all key activities needed to enable the filing of an Investigational New Drug (IND) for URB937 in postoperative pain. Our specific aims are: Aim 1. Synthesis and physicochemical characterization of URB937. We will produce a large-scale lot of URB937 for use in nonclinical pharmacokinetics and toxicology studies. Aim 2. Drug metabolism (DM) and pharmacokinetic (PK) properties of URB937. We will collect the DM-PK data necessary to support the IND filing of URB937. Aim 3. Nonclinical toxicology properties of URB937. We will collect the toxicology data necessary to support the IND filing of URB937. Aim 4. Nonclinical pharmacodynamics of URB937. We will develop a circulating biomarker for peripheral FAAH inhibition, which will be of great value during the clinical development of URB937. The proposed studies will be coordinated by an experienced team of scientists and pharmaceutical professionals, which include Anteana's cofounders, Professor Daniele Piomelli and Dr. Miguel Garcia-Guzman, Professor Andrew Rice (Imperial College, London), a world-recognized leader in pain therapy; along with and independent consultants Dr. Edward Monaghan (Soar Pharmaceutical Development Services: preclinical development); Dr. Fred Reno (toxicology); Dr. William Schmidt (NorthStar Consulting, health economics); Dr. Jason Brittain (JNG Pharmaceutical Consulting, Chemistry, Manufacturing, and Controls); and Dr. Richard Lowenthal (Pacific Link Consulting, regulatory affairs). We expect that the successful completion of our studies will provide the data needed to file an IND for URB937 and allow us to raise the private capital necessary to bring this compound to clinical proof of concept.

 描述（由申请人提供）：疼痛管理是一个重要的未满足的医疗需求。 Anandamide 是一种内源性大麻素介质，在疼痛调节中发挥着重要作用。 先前的研究表明，位于中枢神经系统 (CNS) 之外的内源性大麻素受体发挥着强大的作用。对疼痛引发的调节控制。脂肪酸酰胺水解酶 (FAAH) 可以阻止 anandamide 的生物作用。为了探索 anandamide 在外周疼痛调节中的作用，我们的实验室开发了一种新型的药物。不进入中枢神经系统的 FAAH 抑制剂。此类中的先导化合物称为 URB937，在动物模型中发挥着深远的镇痛作用，表明外周 FAAH 阻断可能为目前第一阶段的疼痛治疗提供一种创新方法。应用表明，URB937 (a) 比目前使用的镇痛药更有效地抑制小鼠术后疼痛；(b) 不会引起这些药物的典型副作用（即， (c) 显示出高度的靶标选择性；(d) 在大鼠中具有优异的口服生物利用度；以及 (e) 在 Ames 试验中不产生遗传毒性作用，并且不会抑制人钾 hERG 通道。术后疼痛的临床前开发的合适候选者，术后疼痛是一种极其常见但仍然服务不足的疼痛状况，本提案的目标是完成实现这一目标所需的所有关键活动。我们的具体目标是： 目标 1. URB937 的合成和理化表征 我们将大规模生产 URB937 用于非临床药代动力学和毒理学研究。目标 2. URB937 的药物代谢 (DM) 和药代动力学 (PK) 特性我们将收集支持 IND 备案所需的 DM-PK 数据。 URB937。目标 3. URB937 的非临床毒理学特性。目标 4. URB937 的非临床药效学。我们将开发一种外周 FAAH 抑制的循环生物标志物。拟议的研究将由经验丰富的科学家和制药专业人士团队协调，其中包括 Anteana 的团队。联合创始人 Daniele Piomelli 教授和 Miguel Garcia-Guzman 博士、世界公认的疼痛治疗领域领军人物 Andrew Rice 教授（伦敦帝国理工学院）以及独立顾问 Edward Monaghan 博士（Soar 药物开发服务：临床前开发） Fred Reno 博士（毒理学）；William Schmidt 博士（NorthStar Consulting，健康经济学）；Jason Brittain 博士（JNG 制药咨询，化学，和 Richard Lowenthal 博士（Pacific Link Consulting，监管事务）我们预计，我们的研究的成功完成将为 URB937 提交 IND 所需的数据，并使我们能够筹集必要的私人资本，将该化合物推向临床证明。的概念。