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. Public Health Relevance Statement Project narrative Non-alcoholic steatohepatitis is a serious liver disease. Our goal is to produce a special blocker of the CB1 receptor to treat this disease. This compound will have two novel characteristics have limited brain exposure and not interfere with base level receptor activity. Both strategies will help to minimize adverse effects.
Project Terms: absorption ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Comparative Study ; Cytochrome P450 ; Cytochrome P-450 ; Cytochrome P-450 Enzyme System ; Cytochrome P450 Family Gene ; P450 ; Diet ; diets ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzymes ; Enzyme Gene ; Europe ; Fatty Liver ; Liver Steatosis ; hepatic steatosis ; Goals ; Human ; Modern Man ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligands ; Lipids ; Liver diseases ; Hepatic Disorder ; hepatic disease ; hepatopathy ; liver disorder ; Alcoholic Liver Diseases ; alcohol induced hepatic injury ; alcohol induced liver disorder ; alcohol induced liver injury ; alcohol-induced hepatic dysfunction ; alcohol-induced liver disease ; alcohol-induced liver dysfunction ; alcohol-mediated liver dysfunction ; alcohol-mediated liver injury ; alcoholic liver injury ; ethanol induced hepatic injury ; ethanol induced liver disorder ; ethanol induced liver injury ; ethanol-induced hepatic dysfunction ; ethanol-induced liver disease ; ethanol-induced liver dysfunction ; ethanol-mediated liver dysfunction ; ethanol-mediated liver injury ; Obesity ; adiposity ; corpulence ; Legal patent ; Patents ; Patients ; Permeability ; Drug Kinetics ; Pharmacokinetics ; Plasma Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Risk ; Rodent ; Rodentia ; Rodents Mammals ; Safety ; Solubility ; Sucrose ; Saccharose ; Testing ; Time ; Tissues ; Body Tissues ; Water ; Hydrogen Oxide ; Body Weight decreased ; Weight Loss ; Weight Reduction ; body weight loss ; wt-loss ; islet amyloid polypeptide ; Insulinoma amyloid peptide ; amlintide ; amylin ; diabetes associated peptide ; insulinoma amyloid polypeptide ; pancreatic amylin ; Generations ; Anhedonia ; base ; Organ ; improved ; Hepatic ; Peripheral ; Benign ; Chronic ; Clinical ; Penetration ; dysphoria ; Withdrawal ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Agonist ; SR 141716A ; SR141716A ; Therapeutic ; Anti-Obesity Drugs ; Antiobesity Agents ; Antiobesity Drugs ; Anti-Obesity Agents ; CB1 ; CB1 Receptor ; CB1R ; Cannabinoid Receptor CB1 ; cannabinoid receptor 1 ; cannabinoid receptor type 1 ; CNR1 gene ; Severities ; Oral ; American ; adipogenesis ; lipogenesis ; lipid biosynthesis ; Receptor Protein ; receptor ; fat metabolism ; lipid metabolism ; exhibitions ; novel ; behavioral test ; behavior test ; Emotional ; Modeling ; Property ; Adverse effects ; insulin sensitivity ; CNS Nervous System ; Central Nervous System ; Neuraxis ; Metabolic syndrome ; acomplia ; zimulti ; rimonabant ; fatty acid oxidation ; behavioral assessment ; Behavior assessment ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Brain region ; Dose ; Data ; Resolution ; Cognitive ; New Agents ; Non-Rodent Model ; Characteristics ; Process ; Development ; developmental ; Behavioral ; pre-clinical ; preclinical ; design ; designing ; Outcome ; Consumption ; Coupled ; clinically relevant ; clinical relevance ; reward processing ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; nonalcoholic steatohepatitis ; NASH ; non-alcohol induced steatohepatitis ; non-alcoholic steato-hepatitis ; non-alcoholic steatohepatitis ; nonalcoholic steato-hepatitis ; endogenous cannabinoid system ; eCB system ; endocannabinoid system ; FDA approved ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; non-drug ; nondrug ; efficacy testing ; Regimen ; screening ; CB1 receptor antagonist ; endocannabinoid signaling ; ECB signaling ; liver development ; efficacy study ; clinical development ; non-alcoholic fatty liver disease ; NAFLD ; non-alcohol fatty liver disease ; non-alcoholic liver disease ; nonalcoholic fatty liver disease ; lead candidate ; in vivo evaluation ; in vivo testing ; forced swim test ; diet-induced obesity ; diet-associated obesity ; diet-related obesity ;
