steatohepatitis

Apararenone (MT-3995) is a receptor antagonist of mineralocorticoid receptor which can be used to treat non-alcoholic steatohepatitis and diabetic nephropathy.

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

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

Efruxifermin, an Fc-FGF21 fusion protein consisting of a human IgG1 Fc domain linked to modified human FGF21, exhibits a prolonged half-life and enhanced receptor affinity compared to its native counterpart. It is utilized in researching non-alcoholic steatohepatitis [1].

Efinopegdutide (JNJ-64565111) is a potent dual agonist for the glucagon-like peptide-1 (GLP-1) and glucagon receptors (GluR), showing efficacy in activating both receptors. It has potential applications in the research of nonalcoholic steatohepatitis (NASH) [1].

ZLY28 is a novel, first-in-class compound with specific intestinal restriction and oral activity, serving as a dual modulator of FXR and FABP1. Additionally, it is a pioneering anti-NASH agent, utilized in the study of nonalcoholic steatohepatitis (NASH) [1].

MGAT2-IN-4 (compound 33) serves as a monoacylglycerol acyltransferase 2 (MGAT2) inhibitor, exhibiting liver metabolic stability. This compound is applicable in obesity, diabetes, and non-alcoholic steatohepatitis (NASH) research [1].

Nimacimab is a recombinant humanized monoclonal antibody. It can improve diabetes and non-alcoholic steatohepatitis.

11,12-DiHETrE, a Cytochrome P450 (P450) eicosanoid and endogenous metabolite, holds potential as a single biomarker for differentiating nonalcoholic fatty liver (NAFL) from nonalcoholic steatohepatitis (NASH) [1] [2]. Additionally, it is utilized in preterm labor research.

BMS-986172 is an orally active, highly selective inhibitor of MGAT2, demonstrating inhibitory concentrations (IC50) of 4.6 nM for human MGAT2 (hMGAT2) and 20 nM for mouse MGAT2 (mMGAT2). It exhibits a half-life (T1/2) greater than 120 minutes in vitro and is known to decrease food intake and body weight. This compound is considered promising for the research of metabolic disorders, including obesity and non-alcoholic steatohepatitis (NASH) [1].

Pemvidutide, a dual GLP-1R/GCGR agonist, significantly lowers body weight, liver fat, and serum lipids, holding promise for non-alcoholic steatohepatitis (NASH) and obesity research [1].

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

2-Methylbutyrylcarnitine, a metabolite of fatty acids, predominantly exists in human and animal blood and urine, resulting from the pyruvate carboxylation pathway. It is notably elevated in the plasma of individuals with steatohepatitis (NASH), serving as a biomarker for diagnosing metabolic diseases [1].

Simtuzumab is a monoclonal antibody against lysyl oxidase-like protein 2 (LOXL2). Simtuzumab can be used to treat primary sclerosing cholangitis (PSC) and is not effective in patients with bridging fibrosis or compensatory cirrhosis caused by non-alcoholic steatohepatitis.

FXR agonist 3, an anti-NASH (Non-Alcoholic Steatohepatitis) agent, functions by activating FXR. It demonstrates anti-fibrogenic activity by inhibiting the expression of COL1A1, TGF-β1, α-SMA, and TIMP1. Additionally, it significantly mitigates liver steatosis and inflammation and enhances the liver fibrosis level [1].

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.

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)

CTPI-2 is an inhibitor of mitochondrial citrate carrier SLC25A1 with(KD : 3.5 μM). CTPI-2 inhibits glycolysis, PPARγ, and its downstream target the glucose transporter GLUT4. CTPI-2 exhibits anti-tumor activity.CTPI-2 halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, and starkly mitigating obesity induced by a high-fat diet.

FXR antagonist 1 is a selective, orally active intestinal FXR antagonist with an IC50 value of 2.1 μM. FXR antagonist 1 antagonises intestinal FXR and selectively inhibits intestinal FXR signalling by feedback activation of hepatic FXR. FXR antagonist 1 can improve liver steatosis, inflammation and fibrosis in the NASH (non-alcoholic steatohepatitis) model and can be used to study NASH.

Ervogastat (PF-06865571) is a potent and well-tolerated diacylglycerol acyltransferase 2 inhibitor. Ervogastat reduces steatosis and hepatic triglyceride levels in non-alcoholic steatohepatitis (NASH).

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.

JT001 (NLRP3-IN-19) is a potent, specific, and orally active NLRP3 inhibitor that impedes the assembly of the NLRP3 inflammasome. This action results in the suppression of cytokine release and prevention of pyroptosis. JT001 is utilized in research on nonalcoholic steatohepatitis and liver fibrosis [1].

NSC 48160, a chemical compound, exhibits inhibitory effects on pancreatic cancer cell proliferation, with half-maximal inhibitory concentrations (IC50s) of 84.3 μM for CPFAC-1 and 94.5 μM for BxPC-3. It also promotes apoptosis in pancreatic cancer cells. Additionally, NSC 48160 has been shown to ameliorate metabolic syndromes, including non-alcoholic steatohepatitis (NASH), obesity, and lipid metabolism disorders [1] [2].

S217879 is a potent and selective activator of NRF2 that disrupts the KEAP1-NRF2 interaction, resulting in significant activation of the NRF2 pathway. This compound is applicable in research on non-alcoholic steatohepatitis (NASH) [1].

BMS-986318 is a potent nonbile acid FXR agonist, displaying EC50 values of 53 nM and 350 nM in FXR Gal4 and SRC-1 recruitment assays, respectively. It exhibits a favorable ADME profile and shows effectiveness in mouse models of liver cholestasis and fibrosis caused by bile duct ligation. BMS-986318 is employed in research focusing on nonalcoholic steatohepatitis.

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).

GIP/GLP-1 dual receptor agonist-1 (compound 4), a receptor agonist for both GIP and GLP-1, shows potential for the research of metabolic disorders and fatty liver diseases, such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) [1].

Glycolithocholic acid sodium salt, the sodium form of Glycolithocholic acid, is a glycine-conjugated secondary bile acid utilized in diagnosing ulcerative colitis (UC), non-alcoholic steatohepatitis (NASH), and primary sclerosing cholangitis (PSC).

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)

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.

PPARα/δ agonist 1 is a potent PPARα/PPARδ dual agonist with EC50 values of 7.0 nM for PPARα and 8.4 nM for PPARδ. PPARα/δ agonist 1 exhibits high selectivity for PPARγ (EC50: 1316.1 nM). agonist 1 has potential for non-alcoholic steatohepatitis studies.

EDP-305, an orally active, potent, and selective agonist of the farnesoid X receptor (FXR), exhibits EC50 values of 34 nM in chimeric FXR within CHO cells and 8 nM in full-length FXR in HEK cells. Demonstrating a potent and consistent antifibrotic effect, EDP-305 is utilized in research related to primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH).

Alismanol M, a protostane-type triterpenoid isolated from the rhizome of Alisma orientale, functions as a farnesoid X receptor (FXR) agonist with an EC50 value of 50.25 μM. It is utilized in researching cholestasis and nonalcoholic steatohepatitis [1].

Leronlimab (PRO 140) is a humanized IgG4 anti-CCR5 monoclonal antibody. leronlimumab has both anti-HIV and anti-tumor activity, inhibiting CCR-mediated HIV-1 virus and cancer cell metastasis in mouse tumor models. Leronlimab can be used to study HIV non-alcoholic steatohepatitis (NASH) and breast cancer.

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.

Docosapentaenoic acid (DPA), a 22-carbon fatty acid primarily found in fish oil, constitutes a minor fraction of the total unsaturated fatty acids in human serum, with concentrations ranging from 0.1% to 1%, which can increase through dietary supplementation. The all-cis-4,7,10,13,16-DPA variant, also known as Austrian acid, represents a specific isomer of DPA and falls into the omega-6 category, synthesized through the elongation and desaturation of arachidonic acid. In conditions such as fatty acid desaturase syndrome, its levels may decrease, potentially influencing development. Furthermore, conditions like nonalcoholic steatohepatitis, a precursor to hepatocellular carcinoma, are marked by enhanced expression of the hepatic elongase very long fatty acid protein 6 and increased concentrations of very long-chain fatty acids, including all-cis-4,7,10,13,16-DPA.

Aldafermin (NGM282), an analog of fibroblast growth factor 19, is utilized in the investigation of nonalcoholic steatohepatitis (NASH) [1].

Pemvidutide (TFA), a GLP-1R/GCGR dual agonist, effectively reduces body weight, liver fat, and serum lipid levels, and is utilized in research on non-alcoholic steatohepatitis (NASH) and obesity [1].

Anti-NASH Agent 1 (Compound 3d), derived from Elafibranor, serves as a strong PPAR-α/δ agonist aimed at treating nonalcoholic steatohepatitis (NASH). At dosages of 3-10 mg/kg over four weeks, this compound ameliorates hyperlipidemia, liver fat degeneration, and inflammation in a methionine-choline deficiency (MCD)-induced NASH mouse model, exhibiting minimal hepatotoxicity while providing substantial hepatic protection [1].

JT001 (NLRP3-IN-19) sodium is a potent, specific, and orally active NLRP3 inhibitor that impedes the assembly of the NLRP3 inflammasome, thus curbing cytokine release and averting pyroptosis. It is utilized in research focused on nonalcoholic steatohepatitis and liver fibrosis [1].

All-cis-4,7,10,13,16-Docosapentaenoic acid (all-cis-4,7,10,13,16-DPA) methyl ester, also known as Osbond acid, is an isomer of DPA and a more lipid-soluble variant of the free acid, primarily found in fish oils as an ω-3, 22-carbon fatty acid. Despite being an ω-6 fatty acid synthesized through the elongation and desaturation of arachidonic acid, its levels can decrease due to fatty acid desaturase syndrome, potentially impacting development. Additionally, increased expression of hepatic elongation of very long fatty acids protein 6 and elevated levels of very long-chain fatty acids, including all-cis-4,7,10,13,16-DPA, are indicative of nonalcoholic steatohepatitis, a condition that precedes hepatocellular carcinoma.

Beinaglutide, a recombinant human GLP-1 (rhGLP-1) polypeptide, exhibits nearly complete homology with human GLP-1 (7–36). It demonstrates dose-dependent effects in improving glycemic control, reducing food intake, delaying gastric emptying, and promoting weight loss. This compound shows promise for research into overweight/obesity and nonalcoholic steatohepatitis (NASH) [1] [2].

QH536 is an effective degrader of HMGCR (EC50: 0.22 μM).QH536 exhibits anti-inflammatory effects and does not have the side effect of inducing intracellular accumulation of cholesterol.QH536 can be used to study cardiovascular disease and non-alcoholic steatohepatitis.

THR-β agonist 4 is a potent agonist of THR-β. THR-β agonist 4 has shown research potential for metabolic diseases such as hyperlipidemia, obesity, hypercholesterolemia, diabetes and other conditions such as steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis and other related conditions and diseases.

THR-β agonist 3 is a potent agonist of THR-β. THR-β agonist 3 has shown research potential for metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis and other related conditions and diseases.

TRβ Agonist 1, a selective and mutation-sensitive thyroid hormone receptor β (TRβ) agonist, demonstrates an EC50 value of 21 nM. It is useful in the research of dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH) [1].

NLRP3-IN-20 (compound 11) is an orally administered inhibitor targeting the NLRP3 inflammasome, exhibiting potent inhibition with an IC50 of 25 nM against IL-1β secretion. It possesses excellent pharmacokinetic properties and has shown significant efficacy in models of non-alcoholic steatohepatitis, fatal septic shock, and colitis [1].

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.

BMS-986339 is an orally active, potent FXR agonist that interacts via H-bond formation with the His298 and ASN287 residues. It is utilized in research focused on primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH) for its anti-fibrosis properties.

THR-β Agonist 6, a selective and orally active compound targeting the thyroid hormone receptor β (THR-β), demonstrates specificity with EC50 values of 0.03 μM for THR-β and 0.22 μM for THR-α. This compound boasts a remarkable liver-to-serum ratio of 93:1 in mouse models, underscoring its efficacy and potential for research in nonalcoholic steatohepatitis (NASH) [1].