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.