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Current Diabetes Reviews

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ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

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Review Article

CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications

Author(s): Saurabh Kumar Gupta and Pushpendra Kumar Tripathi*

Volume 19, Issue 9, 2023

Published on: 07 September, 2022

Article ID: e180822207672 Pages: 9

DOI: 10.2174/1573399819666220818163758

Price: $65

Abstract

The lack of currently available drugs for treating diabetes complications has stimulated our interest in finding new Aldose Reductase inhibitors (ARIs) with more beneficial biological properties. One metabolic method uses aldose reductase inhibitors in the first step of the polyol pathway to control excess glucose flux in diabetic tissues. Computer-aided drug discovery (CADD) is key in finding and optimizing potential lead substances. AR inhibitors (ARI) have been widely discussed in the literature. For example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China. Inhibiting R in patients with severe to moderate diabetic autonomic neuropathy benefits heart rate variability. AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it reduces inflammation and cardiac damage. In summary, these results from animal and human studies strongly indicate that AR can cause cardiovascular complications in diabetes. The current multi-center, large-scale randomized human study of the newly developed powerful ARI may prove its role in diabetic cardiovascular disease to establish therapeutic potential. During the recent coronavirus disease (COVID-19) outbreak in 2019, diabetes and cardiovascular disease were risk factors for severely negative clinical outcomes in patients with COVID19. New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19.

Keywords: Aldose Reductase inhibitors (ARIs), polyol pathway, Computer-aided drug discovery (CADD), Epalrestat, coronavirus disease (COVID-19)

[1]
Verma SK, Rajpoot TK, Gautam MK, Jain A, Thareja S. Design of novel biphenyl-2-thioxothiazolidin-4-one derivatives as potential protein tyrosine phosphatase (PTP)-1B inhibitors using molecular docking study. Lett Drug Des Discov 2016; 13(4): 295-300.
[http://dx.doi.org/10.2174/1570180812666150819002954]
[2]
Suzen S, Buyukbingol E. Recent studies of aldose reductase enzyme inhibition for diabetic complications. Curr Med Chem 2003; 10(15): 1329-52.
[http://dx.doi.org/10.2174/0929867033457377] [PMID: 12871133]
[3]
Reddy AB, Ramana KV. Aldose reductase inhibition: Emerging drug target for the treatment of cardiovascular complications. Recent Adv Cardiovasc Drug Discov 2010; 5(1): 25-32.
[http://dx.doi.org/10.2174/157489010790192683] [PMID: 19886861]
[4]
Verma SK, Thareja S. Molecular docking assisted 3D-QSAR study of benzylidene-2, 4-thiazolidinedione derivatives as PTP-1B inhibitors for the management of type-2 diabetes mellitus. RSC Advances 2016; 6(40): 33857-67.
[http://dx.doi.org/10.1039/C6RA03067J]
[5]
Hex N, Bartlett C, Wright D, Taylor M, Varley D. Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med 2012; 29(7): 855-62.
[http://dx.doi.org/10.1111/j.1464-5491.2012.03698.x] [PMID: 22537247]
[6]
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539-53.
[http://dx.doi.org/10.1002/(SICI)1096-9136(199807)15:7<539:AID-DIA668>3.0.CO;2-S] [PMID: 9686693]
[7]
Oates PJ, Mylari BL. Aldose reductase inhibitors: Therapeutic implications for diabetic complications. Expert Opin Investig Drugs 1999; 8(12): 2095-119.
[http://dx.doi.org/10.1517/13543784.8.12.2095] [PMID: 11139842]
[8]
Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med 2002; 251(2): 87-101.
[http://dx.doi.org/10.1046/j.1365-2796.2002.00932.x] [PMID: 11905595]
[9]
Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med (Berl) 1998; 76(1): 21-31.
[http://dx.doi.org/10.1007/s109-1998-8101-y] [PMID: 9462865]
[10]
Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl 2000; 77: S13-8.
[http://dx.doi.org/10.1046/j.1523-1755.2000.07703.x] [PMID: 10997685]
[11]
Nishikawa T, Edelstein D, Brownlee M. The missing link: A single unifying mechanism for diabetic complications. Kidney Int Suppl 2000; 77: S26-30.
[http://dx.doi.org/10.1046/j.1523-1755.2000.07705.x] [PMID: 10997687]
[12]
Demir Y, Taslimi P. Koçyiğit ÜM, et al. Determination of the inhibition profiles of pyrazolyl-thiazole derivatives against aldose reductase and α-glycosidase and molecular docking studies. Arch Pharm (Weinheim) 2020; 353(12): e2000118.
[http://dx.doi.org/10.1002/ardp.202000118] [PMID: 32761859]
[13]
Sacre JW, Magliano DJ, Shaw JE. Incidence of hospitalization for heart failure relative to major atherosclerotic events in type 2 diabetes: A meta-analysis of cardiovascular outcomes trials. Diabetes Care 2020; 43(10): 2614-23.
[http://dx.doi.org/10.2337/dc20-0654] [PMID: 32958618]
[14]
Bell DSH, Goncalves E. Atrial fibrillation and type 2 diabetes: Prevalence, etiology, pathophysiology and effect of anti-diabetic therapies. Diabetes Obes Metab 2019; 21(2): 210-7.
[http://dx.doi.org/10.1111/dom.13512] [PMID: 30144274]
[15]
Jannapureddy S, Sharma M, Yepuri G, Schmidt AM, Ramasamy R. Aldose reductase: An emerging target for development of interventions for diabetic cardiovascular complications. Front Endocrinol (Lausanne) 2021; 12: 636267.
[http://dx.doi.org/10.3389/fendo.2021.636267] [PMID: 33776930]
[16]
Anil Kumar P, Bhanuprakash Reddy G. Focus on molecules: Aldose reductase. Exp Eye Res 2007; 85(6): 739-40.
[http://dx.doi.org/10.1016/j.exer.2006.08.002] [PMID: 16997295]
[17]
González RG, Barnett P, Aguayo J, Cheng HM, Chylack LT Jr. Direct measurement of polyol pathway activity in the ocular lens. Diabetes 1984; 33(2): 196-9.
[http://dx.doi.org/10.2337/diab.33.2.196] [PMID: 6692996]
[18]
Van Heyningen R. Formation of polyols by the lens of the rat with ‘sugar’ cataract. Nature 1959; 468(4681): 194-5.
[http://dx.doi.org/10.1038/184194b0]
[19]
Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 2005; 26(3): 380-92.
[http://dx.doi.org/10.1210/er.2004-0028] [PMID: 15814847]
[20]
Lee AY, Chung SK, Chung SS. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci USA 1995; 92(7): 2780-4.
[http://dx.doi.org/10.1073/pnas.92.7.2780] [PMID: 7708723]
[21]
Srivastava S, Ramana KV, Tammali R, Srivastava SK, Bhatnagar A. Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells. Diabetes 2006; 55(4): 901-10.
[http://dx.doi.org/10.2337/diabetes.55.04.06.db05-0932] [PMID: 16567509]
[22]
Bhatnagar A, Srivastava SK. Aldose reductase: Congenial and injurious profiles of an enigmatic enzyme. Biochem Med Metab Biol 1992; 48(2): 91-121.
[http://dx.doi.org/10.1016/0885-4505(92)90055-4] [PMID: 1419150]
[23]
Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: The end of an era or the need for different trial designs? Diabetes 1997; 46(2) (Suppl. 2): S82-9.
[http://dx.doi.org/10.2337/diab.46.2.S82] [PMID: 9285505]
[24]
Matsuoka K, Sakamoto N, Akanuma Y, et al. A long-term effect of epalrestat on motor conduction velocity of diabetic patients: ARI-Diabetes Complications Trial (ADCT). Diabetes Res Clin Pract 2007; 77(1) (Suppl. 1): S263-8.
[http://dx.doi.org/10.1016/j.diabres.2007.01.069] [PMID: 17599629]
[25]
Hotta N, Akanuma Y, Kawamori R, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: The 3-year, multicenter, comparative aldose reductase inhibitor-diabetes complications trial. Diabetes Care 2006; 29(7): 1538-44.
[http://dx.doi.org/10.2337/dc05-2370] [PMID: 16801576]
[26]
El-Kabbani O, Carbone V, Darmanin C, et al. Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivity. J Med Chem 2005; 48(17): 5536-42.
[http://dx.doi.org/10.1021/jm050412o] [PMID: 16107153]
[27]
Hotta N, Kakuta H, Ando F, Sakamoto N. Current progress in clinical trials of aldose reductase inhibitors in Japan. Exp Eye Res 1990; 50(6): 625-8.
[http://dx.doi.org/10.1016/0014-4835(90)90104-3] [PMID: 2115451]
[28]
Foppiano M, Lombardo G. Worldwide pharmacovigilance systems and tolrestat withdrawal. Lancet 1997; 349(9049): 399-400.
[http://dx.doi.org/10.1016/S0140-6736(97)80018-9] [PMID: 9033472]
[29]
Cragg GM, Newman DJ. Natural products: A continuing source of novel drug leads. Biochim Biophys Acta 2013; 1830(6): 3670-95.
[http://dx.doi.org/10.1016/j.bbagen.2013.02.008] [PMID: 23428572]
[30]
Lahlou M. The success of natural products in drug discovery. Pharmacol Pharm 2013; 4(3A): 17-31.
[http://dx.doi.org/10.4236/pp.2013.43A003]
[31]
Masand VH, Elsayed NN, Thakur SD, Gawhale N, Rathore MM. Quinoxalinones based aldose reductase inhibitors: 2D and 3D-QSAR analysis. Mol Inform 2019; 38(8-9): e1800149.
[http://dx.doi.org/10.1002/minf.201800149] [PMID: 31131980]
[32]
Vyas B, Singh M, Kaur M, et al. Aldose reductase inhibitors for diabetic complications: Receptor induced atom-based 3D-QSAR analysis, synthesis and biological evaluation. J Mol Graph Model 2015; 59: 59-71.
[http://dx.doi.org/10.1016/j.jmgm.2015.03.005] [PMID: 25911954]
[33]
Vyas B, Singh M, Kaur M, Silakari O, Bahia MS, Singh B. Pharmacophore and dockingbased hierarchical virtual screening for the designing of aldose reductase inhibitors: Synthesis and biological evaluation. Med Chem Res 2016; 25(4): 609-26.
[http://dx.doi.org/10.1007/s00044-016-1510-5]
[34]
Madeswaran A, Umamaheswari M, Asokkumar K, Sivashanmugam T, Subhadradevi V, Jagannath P. Docking studies of aldose reductase inhibitory activity of commercially available flavonoids. Int J Biomed Pharmaceut Sci 2013; 7: 7-11.
[35]
Verma SK, Thareja S. Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors. PLoS One 2017; 12(4): e0175318.
[http://dx.doi.org/10.1371/journal.pone.0175318] [PMID: 28399135]
[36]
Caballero J. 3D-QSAR (CoMFA and CoMSIA) and pharmacophore (GALAHAD) studies on the differential inhibition of aldose reductase by flavonoid compounds. J Mol Graph Model 2010; 29(3): 363-71.
[http://dx.doi.org/10.1016/j.jmgm.2010.08.005] [PMID: 20863730]
[37]
Zhang S-Z, Zheng C, Zhu C-J. Molecular docking and receptor-based 3D-QSAR studies on aromatic thiazine derivatives as selective aldose reductase inhibitors. Wuli Huaxue Xuebao 2015; 31(12): 2395-404.
[http://dx.doi.org/10.3866/PKU.WHXB201510142]
[38]
Nantasenamat C, Monnor T, Worachartcheewan A, Mandi P, Isarankura-Na-Ayudhya C, Prachayasittikul V. Predictive QSAR modeling of aldose reductase inhibitors using Monte Carlo feature selection. Eur J Med Chem 2014; 76: 352-9.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.043] [PMID: 24589490]
[39]
Maccari R, Del Corso A, Giglio M, Moschini R, Mura U, Ottanà R. In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors. Bioorg Med Chem Lett 2011; 21(1): 200-3.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.041] [PMID: 21129963]
[40]
Ramunno A, Cosconati S, Sartini S, et al. Progresses in the pursuit of aldose reductase inhibitors: The structure-based lead optimization step. Eur J Med Chem 2012; 51: 216-26.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.045] [PMID: 22436396]
[41]
Jedziniak JA, Kinoshita JH. Activators and inhibitors of lens aldose reductase. Invest Ophthalmol 1971; 10(5): 357-66.
[PMID: 4397412]
[42]
Gabbay KH, Spack N, Loo S, Hirsch HJ, Ackil AA. Aldose reductase inhibition: Studies with alrestatin. Metabolism 1979; 28(4) (Suppl. 1): 471-6.
[http://dx.doi.org/10.1016/0026-0495(79)90059-3] [PMID: 122298]
[43]
Kikkawa R, Hatanaka I, Yasuda H, et al. Effect of a new aldose reductase inhibitor, (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene]rhodanine (ONO-2235) on peripheral nerve disorders in streptozotocin-diabetic rats. Diabetologia 1983; 24(4): 290-2.
[http://dx.doi.org/10.1007/BF00282716] [PMID: 6407887]
[44]
Steele JW, Faulds D, Goa KL. Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus. Drugs Aging 1993; 3(6): 532-55.
[http://dx.doi.org/10.2165/00002512-199303060-00007] [PMID: 8312678]
[45]
Mizuno K, Kato N, Matsubara A, Nakano K, Kurono M. Effects of a new aldose reductase inhibitor, (2S, 4S)-6-fluoro-2′5′-dioxospiro[chroman-4,4′-imidazolidine]-2-carboxamide (SNK-860), on the slowing of motor nerve conduction velocity and metabolic abnormalities in the peripheral nerve in acute streptozotocin-induced diabetic rats. Metabolism 1992; 41(10): 1081-6.
[http://dx.doi.org/10.1016/0026-0495(92)90289-M] [PMID: 1328819]
[46]
Oka M, Matsumoto Y, Sugiyama S, Tsuruta N, Matsushima M. A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2′ 5′-dioxospiro [chroman-4,4′-imidazolidine]-2-carboxamide (Fidarestat): Its absolute configuration and interactions with the aldose reductase by X-ray crystallography. J Med Chem 2000; 43(12): 2479-83.
[http://dx.doi.org/10.1021/jm990502r] [PMID: 10882376]
[47]
Alexiou P, Nicolaou I, Stefek M, Kristl A, Demopoulos VJ. Design and synthesis of N-(3,5-difluoro-4-hydroxyphenyl) benzenesulfonamides as aldose reductase inhibitors. Bioorg Med Chem 2008; 16(7): 3926-32.
[http://dx.doi.org/10.1016/j.bmc.2008.01.042] [PMID: 18267362]

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