N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice

Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient's progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of...

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Published in:	PloS one Vol. 13; no. 10; p. e0204605
Main Authors:	Bhagat, Hiral A, Compton, Sarah A, Musso, David L, Laudeman, Christopher P, Jackson, Kimberly M P, Yi, Na Young, Nierobisz, Lidia S, Forsberg, Lawrence, Brenman, Jay E, Sexton, Jonathan Z
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 25-10-2018 Public Library of Science (PLoS)
Subjects:	Alcoholism Animal models Animals Anthelmintic agents Anti-Obesity Agents - chemistry Anti-Obesity Agents - pharmacokinetics Anti-Obesity Agents - pharmacology Attenuation Benzamides - chemistry Benzamides - pharmacokinetics Benzamides - pharmacology Bioavailability Biology Biology and Life Sciences Body temperature Cancer Cell Respiration - drug effects Cells, Cultured Derivatives Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diet Diet therapy Diet, High-Fat - adverse effects Disease Models, Animal Dose-Response Relationship, Drug Drug dosages Drug Evaluation, Preclinical Energy expenditure Energy metabolism Escherichia coli - drug effects Ethanolamine Fatty liver Fibrosis Gene mutation Genetic aspects Genotoxicity Glucagon Glucose metabolism Health aspects Health risks Hepatocytes - drug effects Hepatocytes - metabolism High fat diet High-Throughput Screening Assays Homeostasis Humans Infections Insulin Kinases Lipid metabolism Lipids Lipogenesis - drug effects Liver Liver - drug effects Liver - metabolism Liver diseases Male Medicine and Health Sciences Metabolic disorders Metabolic syndrome Metabolism Metabolites Mice Microsomes, Liver - drug effects Microsomes, Liver - metabolism Mitochondria Niclosamide Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism Obesity Obesity - drug therapy Obesity - metabolism Oxidative phosphorylation Patients Phenotypes Phosphorylation Physiology Piperazine Rats, Sprague-Dawley Regulatory agencies Research and Analysis Methods Resistance factors Risk analysis Risk factors Rodents Salmonella Salmonella typhimurium - drug effects Solubility Sperm Substitutes Type 2 diabetes North Carolina Ann Arbor Michigan United States > US Michigan
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Summary:	Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient's progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.
Bibliography:	Competing Interests: We have the following interests. Hiral A. Bhagat, Sarah Compton, David Musso, Christopher Laudeman and Kimberly Palatini are employed by CurlBio, LLC. Jonathan Z. Sexton is the owner of CurlBio and has equity interests in CurlBio, LLC. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0204605