Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

Chianelli, D.; Rucker, Paul V.; Roland, Jason; Tully, David C.; Nelson, John T.; Liu, Xiaodong; Bursulaya, Badry; Hernandez, Eloy D.; Wu, Jane Y.; Prashad, Mahavir; Schlama, Thierry; Liu, Yugang; Chu, Alan; Schmeits, James; Huang, David; Hill, Robert G.; Bao, Dingjiu; Zoll, Jocelyn; Kim, Young; Groessl, Todd; McNamara, Peter; Liu, Bo; Richmond, Wendy; Sancho‐Martinez, Ignacio; Phimister, Andrew; Seidel, H. Martin; Badman, Michael K.; Joseph, Sean B.; Laffitte, Bryan; Molteni, Valentina

doi:10.1021/acs.jmedchem.9b01621

Cited by 72 publications

(41 citation statements)

References 44 publications

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“…New partial FXR agonists (non-bile acids) are currently under development. These include tropifexor (LNJ452) [41,42], EDP-305 [43] and nidufexor (LMB763), of which nidufexor seems the most potent [44]. However, most of the available data on non-bile acid FXR agonists are limited to studies in animal models, and resilient efficacy and safety data in humans are awaited.…”

Section: Lipid Metabolism Gluconeogenesis Hepatokinesmentioning

confidence: 99%

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

2021

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The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium–glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance. Graphical abstract

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Section: Lipid Metabolism Gluconeogenesis Hepatokinesmentioning

confidence: 99%

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

2021

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“…Recently, OCA has been approved for the treatment of primary biliary cholangitis. Furthermore, representatives of both, bile acid analogues and non-steroidal FXR agonists like nidufexor (Chianelli et al, 2020) or tropifexor (Tully et al, 2017) are under clinical investigation for treatment of NAFLD and NASH (Mudaliar et al, 2013;Neuschwander-Tetri et al, 2015). The disease complex of NAFLD/NASH is considered to be a hepatic manifestation of the MetS (Petäjä and Yki-Järvinen, 2016).…”

Section: Seh and Fxrmentioning

confidence: 99%

Multi-Target Approaches in Metabolic Syndrome

2021

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Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed.

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“…Cilofexor for 24 weeks resulted in significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. Other FXR agonists (nidufexor [45], and EDP-305 [46]) have been developed and are in phase 2 trials.…”

Section: Non-bile Acid Fxr Agonist 1) Tropifexor (Ljn-452)mentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming

Jeong

2020

Diabetes Metab J

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The worldwide prevalence of non-alcoholic fatty liver disease is around 25%, and that of nonalcoholic steatohepatitis (NASH) ranges from 1.5% to 6.45%. Patients with NASH, especially those with fibrosis, are at higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Although vitamin E, pioglitazone, and liraglutide improved liver histology in randomized trials, there are currently no Food and Drug Administration-approved drugs for NASH. Five pharmacologic agents-obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol-are being evaluated in large, histology-based phase 3 trials. Within 2 to 4 years, new and effective drugs for the treatment of NASH are expected. Additionally, many phase 2 trials are ongoing for various agents. Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.

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Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

Cited by 72 publications

References 44 publications

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

Multi-Target Approaches in Metabolic Syndrome

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming

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