steatohepatitis

APD668 is a potent GPR119 agonist with EC50 of 2.7 nM and 33 nM for hGPR119 and ratGPR119, respectively.

Denifanstat (FASN-IN-2) is a fatty acid synthase (FASN) inhibitor (IC50=0.052 μM, EC50=0.072 μM) with selective and oral activity. Denifanstat has been used in studies of 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.

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

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.

KHK-IN-5 (Compound 18), a KHK inhibitor, is employed in the study of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and type 2 diabetes (T2DM).

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.

SHS206 (compound 6n) is an orally active mitochondrial uncoupler that decreases triglyceride levels in the liver. Demonstrating in vivo efficacy in a GAN mouse model, SHS206 also exhibits inhibitory effects on metabolic dysfunction-associated steatohepatitis (MASH).

LZ-007 is an agonist of the Farnesoid X receptor (FXR), with an EC50 of 51 nM as determined by TR-FRET assay, and an EC50 of 76 nM in HepG2 cells. It exhibits favorable pharmacokinetic properties in SD rats and can improve metabolic dysfunction-associated steatohepatitis induced by high-fat diets and CCl4 in mice.

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).

FXR HSD17B13 modulator 1 (compound 6) is an effective modulator of FXR HSD17B13, playing a significant role in studies related to metabolic dysfunction-associated steatohepatitis (MASH).

SHO1122147 (Compound 7m) disrupts the mitochondrial electron transport chain, demonstrating mitochondrial uncoupling activity (EC50=3.6 μM). It increases the cellular oxygen consumption rate (OCR=69%) and enhances cellular respiration. Additionally, SHO1122147 is orally active and can be utilized in research related to obesity and metabolic dysfunction-associated steatohepatitis (MASH).

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

BE2647 is a selective inhibitor of the mitochondrial pyruvate carrier (MPC), with an EC50 of 70 nM. It exhibits good metabolic stability in mouse liver microsomes. BE2647 can be utilized in research related to metabolic diseases, metabolic-associated steatotic liver disease (MASLD), or metabolic-associated steatohepatitis (MASH).

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.

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.

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).