Peripheral FAAH as a target for novel analgesics

外周 FAAH 作为新型镇痛药的靶点

• 批准号: 9040444
• 负责人: Daniele Piomelli
• 金额: $ 110.02万
• 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 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040444
• 关键词: Acute Pain; Adverse effects; Ames Assay; Analgesics; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; 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; Operative Surgical Procedures; Opiates; 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; genotoxicity; health economics; innovation; novel; novel therapeutics; peripheral pain; preclinical development; professor; programs; public health relevance; receptor; research clinical testing

 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得到满足的医疗需求。花椒胺是一种内源性大麻素介质，在痛觉调节中发挥重要作用。以往的工作表明，位于中枢神经系统(CNS)外的内源性大麻素受体对疼痛的启动具有强大的调控作用。脂肪酸酰胺水解酶(FAAH)阻止了花生胺的生物学作用。为了探索阿南达胺在疼痛外周调节中的作用，我们的实验室开发了一类新的FAAH抑制剂，它不进入中枢神经系统。这类化合物中的先导化合物URB937在动物模型中具有深刻的镇痛作用，提示外周FAAH阻断可能为疼痛治疗提供一种创新的方法。本申请第一阶段所做的工作已经证明，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(如镇静、便秘、胃损伤)；(C)具有高度的靶向性；(D)在大鼠身上具有极好的口服生物利用度；(E)在Ames‘s试验中不产生基因毒性作用，也不抑制人体钾离子通道。这些结果确定URB937是术后疼痛临床前发展的合适候选者，术后疼痛是一种非常常见但仍未得到充分治疗的疼痛状况。本提案的目标是完成所有必要的关键活动，以便能够提交URB937术后疼痛的研究新药(IND)。我们的具体目标是：目的1.URB937的合成和物化性质。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。目的2.URB937的药物代谢(DM)和药代动力学(PK)特性。我们将收集必要的DM-PK数据，以支持URB937的IND备案。目的3.URB937的非临床毒理学特性。我们将收集所需的毒理学数据，以支持国际标准化组织对URB937的备案。目的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，这将对URB937的临床开发具有重要价值。拟议的研究将由经验丰富的科学家和制药专业人员团队协调，其中包括Anteana的联合创始人Daniele Piomelli教授和Miguel Garcia-Guzman博士、世界公认的止痛治疗领先者Andrew Rice教授和独立顾问Edward Monaghan博士(Soar制药开发服务：临床前开发)、Fred Reno博士(毒理学)、William Schmidt博士(北极星咨询公司，卫生经济学)、Jason Brittain博士(JNG制药咨询公司，化学、制造和控制)和Richard Lowenthal博士(太平洋链接咨询公司，监管事务)。我们预计，我们的研究的成功完成将提供为URB937提交IND所需的数据，并使我们能够筹集必要的私人资本，将这种化合物用于临床概念验证。