Peripheral FAAH as a target for novel analgesics

DESCRIPTIONprovided by applicantPain management is a significant unmet medical needAnandamide is an endocannabinoid mediator that plays important roles in the regulation of painPrevious work has shown that endocannabinoid receptors located outside the central nervous systemCNSexert a powerful regulatory control over pain initiationThe biological actions of anandamide are stopped by the enzymefatty acid amide hydrolaseFAAHTo explore the role of anandamide in the peripheral regulation of painour lab has developed a novel class of FAAH inhibitors that do not enter the CNSThe lead compound in this classcalled URBexerts profound analgesic effects in animal modelssuggesting that peripheral FAAH blockade may offer an innovative approach to pain therapyWork done during the Phaseof the present application has demonstrated that URBasuppresses postoperative pain in mice more effectively than do currently used analgesicsbdoes not cause side effects typical of those drugsi esedationconstipationgastric damagecshows a high degree of target selectivitydhas excellent oral bioavailability in ratsandeexerts no genotoxic effcts in the Amesandapostest and does not inhibit the human potassium hERG channelThese results identify URBas a suitable candidate for preclinical development in postoperative painan extremely common but still underserved pain conditionThe objective of present proposal is to complete all key activities needed to enable the filing of an Investigational New DrugINDfor URBin postoperative painOur specific aims areAimSynthesis and physicochemical characterization of URBWe will produce a large scale lot of URBfor use in nonclinical pharmacokinetics and toxicology studiesAimDrug metabolismDMand pharmacokineticPKproperties of URBWe will collect the DM PK data necessary to support the IND filing of URBAimNonclinical toxicology properties of URBWe will collect the toxicology data necessary to support the IND filing of URBAimNonclinical pharmacodynamics of URBWe will develop a circulating biomarker for peripheral FAAH inhibitionwhich will be of great value during the clinical development of URBThe proposed studies will be coordinated by an experienced team of scientists and pharmaceutical professionalswhich include Anteanaandapos s cofoundersProfessor Daniele Piomelli and DrMiguel Garcia GuzmanProfessor Andrew RiceImperial CollegeLondona world recognized leader in pain therapyalong with and independent consultants DrEdward MonaghanSoar Pharmaceutical Development Servicespreclinical developmentDrFred RenotoxicologyDrWilliam SchmidtNorthStar Consultinghealth economicsDrJason BrittainJNG Pharmaceutical ConsultingChemistryManufacturingand Controlsand DrRichard LowenthalPacific Link Consultingregulatory affairsWe expect that the successful completion of our studies will provide the data needed to file an IND for URBand allow us to raise the private capital necessary to bring this compound to clinical proof of conceptPUBLIC HEALTH RELEVANCECurrent painkillers work well in only about one quarter of the patients who take themand can cause a variety of negative effectsfor examplesedation and addictionby acting on cells of the brainOur lab has recently discovered a new class of medicationscalled `peripheral FAAH inhibitorsandaposwhich cannot enter the brain yet produce powerful pain suppression in experimental modelsHerewe propose a series of studies that will enable the clinical testing of the lead compound in this class for the treatment of acute pain after surgery