Pregnane X Receptor (PXR) Antagonists for Non-Alcoholic Fatty Liver Disease

DESCRIPTION provided by applicant Non Alcoholic Fatty Liver Disease NAFLD is a malady of increasing prevalence because of the growing population of individuals with obesity metabolic syndrome and diabetes This multifactorial disorder due to both environmental and genetic factors affects of Americans with a prevalence of nearly in obese individuals NAFLD can lead to non alcoholic steatohepatitis NASH with a prevalence of in persons with obesity and NASH in turn can lead to hepatocellular carcinoma and cirrhosis The pregnane X receptor PXR has emerged as a potential target for treatment of NAFLD as activation of this receptor results in hepatic steatosis in animal models We have identified and characterized novel human pregnane X receptor antagonist FLB that specifically disrupts the function of activated agonist ligand bound PXR but does not inhibit basal levels of PXR activity This compound has shown to be a selective PXR antagonist in a variety of in vitro and in vivo models More specifically and importantly FLB was able to statistically improve an important disease component hepatocyte ballooning in a murine NAFLD model However the potency and certain drug properties of FLB need to be improved in order for this compound to be considered a viable predevelopment candidate We will realize these goals by accomplishing the following specific aims Aim Identify structure activity relationships SAR for allosteric antagonism of PXR to improve potency and ADME PK properties The goals of this aim are to increase PXR antagonist potency and selectivity as assessed by complementary in vitro assays already established in the Mani lab Our objective is to reduce the IC values in each of these assays into the sub micromolar range Aim Evaluate ADME PK properties for PXR antagonists meeting criteria of Aim We will explore potential drug properties by obtaining in vitro absorption distribution metabolism and excretion ADME data for up to compounds One or two of the most promising compounds will be evaluated for pharmacokinetic PK parameters in mice IV administration to determine in vivo terminal half life volume of distribution and clearance These goals will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center Inc www fc cdci com the PXR structural biology expertise of Collaborations in Chemistry and the extensive expertise of the Mani Lab at the Albert Einstein College of Medicine in the preclinical aspects of PXR modulators Once we achieve the aims of this proposal we will be well positioned to transition into a lead optimization and full drug development program as part of the more extensive Phase II SBIR period of study where our goals would be to find preclinical drug candidates targeting PXR that we can evaluate in detailed NAFLD models under oral administration PUBLIC HEALTH RELEVANCE Non Alcoholic Fatty Liver Disease NAFLD is a malady of increasing prevalence in the US and other western countries with a prevalence of near in obese individuals NAFLD can lead to non alcoholic steatohepatitis NASH with a prevalence of in persons with obesity and NASH in turn can lead to hepatocellular carcinoma and cirrhosis The pregnane X receptor PXR has emerged as a potential target for treatment of NAFLD and we have identified and characterized novel human PXR antagonists one that has shown activity in a murine model of NASH In this proposal we will improve upon our existing PXR antagonists to find safe therapeutic agents for NAFLD NASH