Wa Cheng, Cong Chen, Xiangduan Tan
College of Pharmacy, Guilin Medical University, Guilin, 541199, Guangxi, China
Non-alcoholic steatohepatitis is a clinical syndrome with pathological changes similar to alcoholic steatohepatitis without a history of excessive alcohol consumption, and is a key stage of reversible progression to liver fibrosis, which can further develop into malignant diseases such as cirrhosis or even liver cancer if preventive measures are not taken. The pathogenesis of NASH is complex, and there are no any effective drugs for NASH. It is difficult for single-target drugs to achieve good therapeutic effects, and are accompanied by strong side effects, and many of them are terminated in the clinical trial stage. Multi-target drugs are not easy to produce drug resistance, and can exert synergistic effects on multiple targets to maximize drug efficacy and minimize adverse side effects, and has a good effect on the treatment of complex diseases. This article summarizes the multi-target drugs for the treatment of NASH, and provides a reference for finding new drugs for the treatment of NASH.
Non-alcoholic Steatohepatitis, Multi-target Drugs, Multi-target Agonists, Dual Antagonists
Wa Cheng, Cong Chen, Xiangduan Tan. Research Progress of Multi-Target Drugs in the Treatment of Non-Alcoholic Steatohepatitis. International Journal of Frontiers in Medicine (2022), Vol. 4, Issue 10: 24-29. https://doi.org/10.25236/IJFM.2022.041005.
 Hashimoto E, Taniai M, Tokushige K. Characteristics and diagnosis of NAFLD/NASH [J]. J Gastroenterol Hepatol, 2013, 28 (4): 64-70.
 Kumar R, Priyadarshi R N, Anand U. Non-alcoholic fatty liver disease: growing burden, adverse outcomes and associations [J]. J Clin Transl Hepatol, 2020, 8(1): 76-86.
 Aly F Z, Kleiner D. Update on fatty liver disease and steatohepatitis [J]. Adv Anat Pathol, 2011, 18(4): 294-300.
 Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome [J]. Best Pract Res Clin Gastroenterol, 2014, 28(4): 637-53.
 Povero D, Yamashita H, Ren W, et al. Characterization and Proteome of Circulating Extracellular Vesicles as Potential Biomarkers for NASH [J]. Hepatol Commun, 2020, 4(9): 1263-1278.
 Neuschwander-Tetri B A. Non-alcoholic fatty liver disease [J]. BMC Med, 2017, 15(1): 45.
 Patton H M, Sirlin C, Behling C, et al. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research [J]. J Pediatr Gastroenterol Nutr, 2006, 43(4): 413-427.
 Faienza M F, Chiarito M, Molina-Molina E, et al. Childhood obesity, cardiovascular and liver health: a growing epidemic with age [J]. World J Pediatr, 2020, 16(5): 438-445.
 Eskridge W, Vierling J M, Gosbee W, et al. Screening for undiagnosed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): A population-based risk factor assessment using vibration controlled transient elastography (VCTE) [J]. PLoS One, 2021, 16(11): e0260320.
 Yan M, Man S, Ma L, et al. Comprehensive molecular mechanisms and clinical therapy in nonalcoholic steatohepatitis: An overview and current perspectives [J]. Metabolism, 2022, 134: 155264.
 Noureddin M, Sanyal A J. Pathogenesis of NASH: the impact of multiple pathways [J]. Curr hepatol rep, 2018, 17(4): 350-360.
 Drescher H K, Weiskirchen S, Weiskirchen R. Current status in testing for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [J]. Cells, 2019, 8(8): 845.
 Petroni M L, Brodosi L, Bugianesi E, et al. Management of non-alcoholic fatty liver disease [J]. BMJ, 2021, 372: 4747
 Vuppalanchi R, Noureddin M, Alkhouri N, et al. Therapeutic pipeline in nonalcoholic steatohepatitis [J]. Nat Rev Dis Primers, 2021, 18(6): 373-392.
 Qiu Q, Wang W, Zhao X, et al. Design, synthesis and structure-activity relationship studies of novel partial FXR agonists for the treatment of fatty liver [J]. Bioorg Chem. 2020, 4: 104262.
 Petrelli A, Giordano S. From single- to multi-target drugs in cancer therapy: when a specificity becomes an advantage [J]. Curr Med Chem, 2008, 15: 422−432.
 Fiorucci S, Biagioli M, Distrutti E. Future trends in the treatment of non-alcoholic steatohepatitis [J]. Pharmacol Res, 2018, 134: 289-298.
 Filozof C, Goldstein B J, Williams R N, et al. Non-alcoholic steatohepatitis: limited available treatment options but promising drugs in development and recent progress towards a regulatory approval pathway [J]. Drugs, 2015, 75(12): 1373-1392.
 Cox SL. Tesaglitazar: a promising approach in type 2 diabetes [J]. Drugs Today (Barc), 2006; 42(3): 139-46.
 Jain N, Bhansali S, Kurpad A V, et al. Effect of a Dual PPAR α/γ agonist on Insulin Sensitivity in Patients of Type 2 Diabetes with Hypertriglyceridemia-Randomized double-blind placebo-controlled trial [J]. Sci Rep, 2019, 9(1): 1-9.
 Pai V, Paneerselvam A, Mukhopadhyay S, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V) [J]. J Diabetes Sci Technology, 2014, 8(1): 132-141.
 Kaul U, Parmar D, Manjunath K, et al. New dual peroxisome proliferator activated receptor agonist—Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence [J]. Cardiovasc Diabetol, 2019, 18(1): 1-11.
 Jani R H, Pai V, Jha P, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI) [J]. Diabetes Technol Ther, 2014, 16(2): 63-71.
 Joshi SR. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin Pharmacother [J]. 2015; 16(4): 597-606.
 Jain M R, Giri S R, Bhoi B, et al. Dual PPAR α/γ agonist Saroglitazar improves liver histopathology and biochemistry in experimental NASH models [J]. Liver Int, 2018, 38(6): 1084-1094.
 Katsiki N, Mantzoros C. Making progress towards a better pathophysiological understanding and more promising therapeutic options for treating non-alcoholic steatohepatitis (NASH)/DASH (dysmetabolism associated steatohepatitis) [J]. Metabolism, 2021, 114:154333
 Feng Z, Xiang J, Liu H, et al. Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis [J]. J Med Chem, 2022, 65(3): 2571-2592.
 Cariou B, Zaïr Y, Staels B, et al. Effects of the new dual PPARα/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism [J]. Diabetes Care, 2011, 34(9): 2008-2014.
 Ratziu V, Harrison S A, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator− activated receptor− α and− δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening [J]. Gastroenterology, 2016, 150(5): 1147-1159.
 SWesterouen Van Meeteren M J, Drenth J P H, Tjwa E T T L. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH) [J]. Expert Opin Investig Drugs, 2020, 29(2): 117-123.
 Zarei M, Aguilar-Recarte D, Palomer X, et al. Revealing the role of peroxisome proliferator-activated receptor β/δ in nonalcoholic fatty liver disease [J]. Metabolism, 2021, 114: 154342.
 Pierre B, Elisabetta B, Vlad R, et al. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study [J]. Contemp Clin Trials, 2020, 98: 106170.
 Pan Q, Lin S, Li Y, et al. A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis [J]. EBioMedicine, 2021, 63: 103202.
 Nagata N, Chen G, Xu L, et al. An Update on the Chemokine System in the Development of NAFLD [J]. Medicina, 2022, 58(6): 761.
 Krenkel O, Puengel T, Govaere O, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis [J]. Hepatology, 2018, 67(4): 1270-1283.
 Fiorucci S, Rapacciuolo P, Fiorillo B, et al. Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease [J]. Front Pharmacol, 2022, 13: 858137.
 Guo Y S, Guo Z R. Design of multiple targeted drugs [J]. Acta Pharm Sin, 2009, 44(3): 276-281.
 Lipinski C A, Lombardo F, Dominy B W, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings [J]. Adv Drug Deliv Rev, 1997, 23(1-3): 3-25.