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

Abstract

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.

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“…Oxygen consumption rate experiments were performed by the CLARIOstar microplate reader (BMG LABTECH, Germany) as previously described [72,73]. In brief, CMs were plated in 96-well assay plates with a density of 30,000 per well in Culture medium.…”

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“…This dose was found to lead to serum C max ranging from 0.8 to 18 μM (37). In CD1 mice, IP injection of niclosamide at 10 mg/kg single dose (the otoprotective dose for our NIHL and CIHL) resulted in a C max of 40 μM (38). In contrast, 120 mg/kg single dose of niclosamide via oral gavage in mice led to a serum C max at 2 μM at 1 hour, suggesting oral delivery in mice is not optimal (lower bioavailability than in humans) (39).…”

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“…Another one, sorafenib, is used to treat hepatic cancer [ 27 , 28 ]. Niclosamide was shown to work on mice kept on a high-fat diet to prevent obesity [ 29 ]. Pre-clinical studies also demonstrated that a recently described uncoupler, Bam15, is efficient in protecting mice against obesity and improving glycemic control [ 30 ].…”