Peripheral FAAH as a target for novel analgesics

 描述（由申请人提供）：疼痛管理是一项重大未满足的医疗需求。大麻素是一种内源性大麻素介质，在疼痛的调节中发挥重要作用。先前的研究表明，位于中枢神经系统（CNS）外的内源性大麻素受体对疼痛的发生具有强大的调节控制作用。花生四烯酸酰胺的生物学作用被脂肪酸酰胺水解酶（FAAH）终止。为了探索大麻素在疼痛的外周调节中的作用，我们实验室开发了一类不进入CNS的新型FAAH抑制剂。这一类的先导化合物，称为URB 937，在动物模型中发挥了深刻的镇痛作用，表明外周FAAH阻滞可能提供一种创新的疼痛治疗方法。在本申请的第1阶段期间进行的工作已经证明URB 937（a）比目前使用的镇痛剂更有效地抑制小鼠的术后疼痛;（B）不引起那些药物的典型副作用（即，镇静、便秘、胃损伤）;（c）显示高度的靶向选择性;（d）在大鼠中具有优异的口服生物利用度;和（e）在艾姆斯试验中不产生遗传毒性作用，并且不抑制人钾hERG通道。这些结果将URB 937确定为用于术后疼痛的临床前开发的合适候选物，这是一种非常常见但仍然服务不足的疼痛状况。本提案的目的是完成URB 937用于术后疼痛的研究性新药（IND）备案所需的所有关键活动。我们的具体目标是：目标1。URB 937的合成和物理化学表征。我们将生产大规模批次的URB 937，用于非临床药代动力学和毒理学研究。目标二。URB 937的药物代谢（DM）和药代动力学（PK）特性。我们将收集支持URB 937 IND申报所需的DM-PK数据。目标3. URB 937的非临床毒理学特性。我们将收集支持URB 937 IND申报所需的毒理学数据。目标4。URB 937的非临床药效学。我们将开发外周FAAH抑制的循环生物标志物，这将在URB 937的临床开发期间具有重要价值。拟议的研究将由一个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，Andrew Rice教授（帝国理工学院，伦敦），世界公认的疼痛治疗的领导者;沿着和独立顾问爱德华·莫纳汉博士（Soar Pharmaceutical Development Services：临床前开发）; Fred里诺博士William施密特博士（NorthStar Consulting，卫生经济学）; Jason Brittain博士（JNG Pharmaceutical Consulting，化学、生产和控制）;和Richard Lowenthal博士（Pacific Link Consulting，法规事务）。我们希望我们的研究的成功完成将提供提交URB 937 IND所需的数据，并使我们能够筹集必要的私人资本，使这种化合物进入临床概念验证。

 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.