THERAPEUTIC STRATEGY FOR NASH - ABSTRACT: THERAPEUTIC STRATEGY FOR NASH THE OVERALL GOAL OF THIS PROJECT IS TO IDENTIFY FOR CLINICAL DEVELOPMENT A PERIPHERALLY SELECTIVE NEUTRAL ANTAGONIST OF THE CB1 RECEPTOR FOR NON-ALCOHOLIC STEATOHEPATITIS (NASH). NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) ASSOCIATED WITH METABOLIC SYNDROME (METS) CAN PROGRESS TO NASH, WHICH IS A SERIOUS DISEASE WITHOUT AN FDA- APPROVED DRUG. THERE IS A STRONG CORRELATION BETWEEN SEVERITY OF NAFLD AND DEVELOPMENT OF NASH, WHICH INDICATE THAT DECREASING FATTY LIVER (STEATOSIS) IS A LEGITIMATE STRATEGY FOR NASH. COMPOUNDS THAT ANTAGONIZE THE CB1 RECEPTOR PROVIDE MANY BENEFITS IN METS THROUGH BOTH CENTRAL NERVOUS SYSTEM (CNS) AND PERIPHERAL MECHANISMS. IMPORTANTLY, RESOLUTION OF NAFLD IS ACHIEVABLE BY TARGETING HEPATIC CB1 RECEPTORS, THEREBY DECREASING DE NOVO LIPOGENESIS AND INCREASING FATTY ACID OXIDATION. COMPETITIVE ORTHOSTERIC ANTAGONISTS CAN BE EITHER INVERSE AGONISTS THAT BLOCK BASAL RECEPTOR ACTIVITY OR NEUTRAL/SILENT ANTAGONISTS THAT ARE DEVOID OF THIS EFFECT. PREVIOUS ATTEMPTS TO TARGET CB1 USING INVERSE AGONISTS LED TO PSYCHIATRIC ADVERSE EFFECTS IN SOME PATIENTS AS THE CB1 RECEPTOR IS INVOLVED IN REWARD PROCESSING WITHIN THE CNS. SUPPRESSION OF BASAL RECEPTOR ACTIVITY POSSIBLY CAUSED EXACERBATION OF DYSPHORIC EFFECTS. PRESENTLY, EFFORTS ARE UNDERWAY TO PRODUCE CNS-SPARING INVERSE AGONISTS TO TARGET PERIPHERAL CB1 RECEPTORS. HOWEVER, A COMPLICATING FACTOR WITH THIS STRATEGY IS THAT THE BLOOD-BRAIN BARRIER THAT PROTECTS THE BRAIN IS NOT CONTINUOUS AND CHRONIC USE OF PERIPHERAL INVERSE AGONISTS STILL HAS THE POSSIBILITY OF PRODUCING ADVERSE EFFECTS. ARTIAM BIO HAS PRODUCED NEUTRAL ANTAGONISTS OF THE CB1 RECEPTOR WITH LIMITED BRAIN PENETRATION. THESE COMPOUNDS HAVE THE DUAL ADVANTAGE OF REDUCED BRAIN PENETRATION COUPLED WITH LACK OF SUPPRESSIVE EFFECTS ON BASAL RECEPTOR ACTIVITY. THIS APPROACH REPRESENTS A MUCH-IMPROVED STRATEGY FOR TARGETING THE CB1 RECEPTOR FOR NASH AND OTHER IMPORTANT DISEASES. THREE AIMS ARE PROPOSED: (1) ADMET CHARACTERIZATION OF THE LIGANDS, OFF-TARGET RECEPTOR SCREENING AND PHARMACOKINETIC PROFILING. (2) ESTABLISH EFFICACY BY TESTING ARTIAM'S BEST COMPOUND IN A DIET-INDUCED MODEL OF NASH THAT IS RELEVANT TO THE HUMAN CONDITION. (3) BEHAVIORAL TESTING OF THE LEAD CANDIDATE IN TWO DIFFERENT ASSAYS USING A CHRONIC DOSING REGIMEN TO ESTABLISH AN ACCEPTABLE SAFETY PROFILE COMPARED TO A CLASSICAL INVERSE AGONIST OF CB1. SUCCESSFUL COMPLETION OF THESE STUDIES WILL LEAD TO IDENTIFICATION OF A FIRST IN CLASS, BEHAVIORALLY DE-RISKED, CLINICAL DEVELOPMENT CANDIDATE FOR NASH TARGETING THE CB1 RECEPTOR.