Non-alcoholic steatohepatitis

CP-24879 hydrochloride (CP-24879 HCl), a Δ5D/Δ6D dual-inhibitor, can significantly reduce intracellular lipid accumulation and inflammatory injury in hepatocytes. CP-24879 hydrochloride exhibits superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes.

Resmetirom (MGL-3196) is a THR-β agonist (EC50=0.21 μM), with high selectivity and oral activity. Resmetirom can be used in the research of non-cirrhotic and non-alcoholic steatohepatitis.

INT-767 is a potent farnesoid X receptor (FXR)/TGR5 dual agonist that prevents NASH and promotes visceral adipose brown lipogenesis and mitochondrial function for the study of non-alcoholic steatohepatitis.

Apararenone (MT-3995) is a mineralocorticoid receptor antagonist indicated for the treatment of non-alcoholic steatohepatitis and diabetic nephropathy.

Berberine ursodeoxycholate (HTD1801) is an orally effective hypolipidemic agent, an ionic salt of Berberine and Ursodeoxycholic acid.Berberine ursodeoxycholate has a wide range of metabolic activity and significantly reduces liver fat content. Berberine ursodeoxycholate has been used in studies of hyperlipidemia, non-alcoholic steatohepatitis (NASH) and diabetes.

Nivocasan Intermediate is an intermediate of Nivocasan. Nivocasan (GS-9450) is a pan-caspase inhibitor used in the study of HCV infection and non-alcoholic steatohepatitis.

DB1976 dihydrochloride (DB1976 2HCl) , a transcription factor PU.1 inhibitor with potential anti-inflammatory activity, slowed down inflammation and fibrosis and improved glucose homeostasis and dyslipidemia in mice in in vivo experiments.DB1976 dihydrochloride promotes apoptosis and may be used in studies of metabolic dysfunction and non-alcoholic steatohepatitis.

Volixibat is a highly selective and competitive apical sodium-dependent bile acid transporter inhibitor. Volixibat has the potential for treatment for non-alcoholic steatohepatitis.

HPG1860, an agonist of the farnesoid X receptor (FXR), induces luminescence in reporter gene assays utilizing HEK293T cells expressing human FXR, with an EC50 value of 18 nM. In vivo studies demonstrate that HPG1860 (administered at 1, 3, or 10 mg/kg daily) reduces serum alanine aminotransferase (ALT) and total cholesterol levels in a mouse model of non-alcoholic steatohepatitis (NASH), which was induced by a high-fat diet and carbon tetrachloride (CCl4). Additionally, this compound decreases hepatic inflammation, fat levels, and fibrosis.

LH10 is an FXR agonist based on fexaramine, with an EC50 of 0.14 μM. It offers hepatoprotective effects, mitigating conditions such as cholestasis induced by alpha naphthylisothiocyanate (ANIT), acute liver injury caused by APAP, and non-alcoholic steatohepatitis (NASH).

GLP-1 receptoragonist 16 (Example 53) is a GLP-1 agonist applicable for research in diabetes, obesity, or diseases related to non-alcoholic steatohepatitis.

NLRP3-IN-70 (Compound 5m) is an inhibitor of the NLRP3 inflammasome with low oral bioavailability. It binds directly to the NACHT domain of the NLRP3 protein, thereby blocking its interaction with ASC, which inhibits ASC oligomerization and the assembly of the NLRP3 inflammasome. NLRP3-IN-70 is applicable in studies on sepsis and non-alcoholic steatohepatitis.

THR-β agonist 2 diacetate (Compound 3) is a potent THR-β agonist with potential applications in researching metabolic disorders such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes, as well as other conditions like steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, and other related diseases and conditions.

GLP-1R modulator-1 (Compound 384) is a potent and orally active selective agonist of the glucagon-like peptide-1 receptor (GLP-1R). It activates G protein-coupled signaling, leading to increased intracellular cAMP levels, enhanced insulin secretion, delayed gastric emptying, and reduced appetite. GLP-1R modulator-1 holds potential for research in type 2 diabetes, obesity, and non-alcoholic steatohepatitis (NASH).

ACC-IN-1 (Compound B1) is an allosteric inhibitor of acetyl-CoA carboxylase (ACC). It targets ACC to regulate lipid metabolism, potentially improving liver steatosis and inflammation associated with non-alcoholic steatohepatitis (NASH).

HSD17B13-IN-105 (Compound EX.87) is a selective inhibitor of 17β-hydroxysteroid dehydrogenase 13 (17BHSD13) with an IC50 value of 0.036 μM, demonstrating high selectivity over 17BHSD4, which has an IC50 value of 31.5 μM. HSD17B13-IN-105 shows potential for research in liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

TBPH exacerbates liver steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) mouse models. It induces phospholipid metabolism disorders, reducing cardiolipin (CL) and phosphatidylserine (PS) levels. TBPH impairs endoplasmic reticulum-mitochondria (ER-Mito) contact, leading to mitochondrial dysfunction. Additionally, TBPH causes lung injury through mitochondrial-derived ds-DNA-mediated inflammatory responses. TBPH is utilized to study the role of MFN2-mediated ER-Mito contact in lipid metabolism homeostasis.

GLP-1R agonist 34 (Compound 1) is an orally active small molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R). It enhances insulin secretion, suppresses glucagon release, and slows gastric emptying, thereby effectively reducing blood glucose levels. GLP-1R agonist 34 holds potential for research into metabolic disorders such as type 2 diabetes, obesity, and non-alcoholic steatohepatitis (NASH).

Glycolithocholic acid (Lithocholic acid glycine conjugate) is a glycine conjugate of lithocholic acid.

SHS4121705 is an orally bioavailable mitochondrial uncoupler.1It increases oxygen consumption rate in L6 rat myoblast cells with an EC50value of 4.3 μM. SHS4121705 (25 mg/kg per day in the diet) reduces hepatic steatosis, liver triglyceride levels, and plasma alanine aminotransferase (ALT) levels in Stelic animal model (STAM) mice, a model of non-alcoholic steatohepatitis (NASH). 1.Salamoun, J.M., Garcia, C.J., Hargett, S.R., et al.6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol derivatives as efficacious mitochondrial uncouplers in STAM mouse model of nonalcoholic steatohepatitisJ. Med. Chem.63(11)6203-6224(2020)

MBX-8025 is an agonist of peroxisome proliferator-activated receptor δ (PPARδ).1 It is greater than 750- and 2,500-fold selective for PPARδ over PPARα and PPARγ. MBX-8025 (10 mg/kg per day for eight weeks) reduces increases in fasting blood glucose and serum insulin levels, and decreases insulin resistance in Alms1 mutant (foz/foz) mice fed an atherogenic diet as a model of diet-induced obesity, type 2 diabetes, and non-alcoholic steatohepatitis (NASH).2 It also decreases serum alanine transaminase (ALT), as well as serum and hepatic cholesterol and triglyceride, levels and reduces markers of NASH in the same model. |1. Bays, H.E., Schwartz, S., Littlejohn, T., 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-δ agonist: Lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96(9), 2889-2897 (2011).|2. Haczeyni, F., Wang, H., Barn, V., et al. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol. Commun. 1(7), 663-674 (2017).

ZLY032 is a dual agonist of free fatty acid receptor 1 (FFAR1/GPR40; EC50= 68 nM in a FLIPR assay) and peroxisome proliferator-activated receptor δ (PPARδ; EC50= 102 nM in a reporter assay).1It is selective for FFAR1 and PPARδ over PPARα and PPARγ (EC50s = >10 μM for both). ZLY032 (40 mg/kg, twice per day) reduces blood glucose levels in an oral glucose tolerance test and decreases plasma total cholesterol and triglyceride levels in theob/obmouse model of metabolic disease.2It reduces hepatic steatosis and plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a methionine and choline-deficient diet at the same dose. 1.Li, Z., Chen, Y., Zhou, Z., et al.Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agentsEur. J. Med. Chem.164352-365(2019) 2.Li, Z., Zhou, Z., Hu, L., et al.ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosisPharmacol Res.159105035(2020)

2-Oleoylglycerol is a lipid found in palm kernel, sunflower seed and rice bran.2-Oleoylglycerol acts as a GPR119 agonist with neuroprotective effects and induces secretion of glucagon-like peptide 1 (GLP-1).2-Oleoylglycerol is used in the modelling of non-alcoholic steatohepatitis.

THR-β agonist 2 is a potent agonist of THR-β with potential for studies of metabolic diseases (e.g., obesity, hyperlipidaemia, hypercholesterolaemia, diabetes, steatosis, non-alcoholic steatohepatitis [NASH], atherosclerosis, and other related conditions).