Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?

Ballekova, Jana; Soltesova-Prnova, M; Májeková, Magdaléna; Štefek, Milan

doi:10.33549/physiolres.933516

Cited by 8 publications

(6 citation statements)

References 42 publications

(22 reference statements)

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“…There are few reports about the role of aldo-keto reductases in inflammation. Aldo-keto reductase was found to reduce peroxidation derived lipid aldehydes, such as 4-hydroxytrans-2-nonenal and their glutathione conjugates, to corresponding alcohols, 1,4-dihydroxy-nonene and glutathionyl-1,4-dihydroxynonene, respectively, which take part in the inflammatory signaling 36 . Inhibition of aldose reductase was found to significantly prevent the transfer of the inflammatory signals induced by multiple factors including allergens, cytokines, growth factors, endotoxins, high glucose, and autoimmune reactions at the cellular level as well as in animal models 37 .…”

Section: Discussionmentioning

confidence: 99%

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Xu¹,

Gao²,

et al. 2020

Preprint

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Background: The outbreak of SARS CoV-2 has caused ever-increasing attention and public panic all over the world. Currently, there is no specific treatment against the SARS CoV-2. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. Previous studies found that indomethacin has the ability to inhibit the replication of several unrelated DNA and RNA viruses, including SARS-CoV.Methods: SARS CoV-2 pseudovirus-infected African green monkey kidney VERO E6 cells treated with different concentrations of indomethacin or aspirin at 48 hours post infection (p.i). The level of cell infection was determined by luciferase activity. Anti-coronavirus efficacy in vivo was confirmed by evaluating the time of recovery in canine coronavirus (CCV) infected dogs treated orally with 1mg/kg body weight indomethacin.Results: We found that indomethacin has a directly and potently antiviral activity against the SARS CoV-2 pseudovirus (reduce relative light unit to zero). In CCV-infected dogs, recovery occurred significantly sooner with symptomatic treatment + oral indomethacin (1 mg/kg body weight) daily treatments than with symptomatic treatment + ribavirin (10-15 mg/kg body weight) daily treatments (P =0.0031), but was not significantly different from that with symptomatic treatment + anti-canine coronavirus serum + canine hemoglobin + canine blood immunoglobulin + interferon treatments (P =0.7784). Conclusion:The results identify indomethacin as a potent inhibitor of SARS CoV-2.

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Section: Discussionmentioning

confidence: 99%

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Xu¹,

Gao²,

et al. 2020

Preprint

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“…present a promising therapeutic approach to treat variety of diabetic complications and inflammatory disorders including some types of cancers related to chronic inflammation. 23,25 ARIs, such as acetic acid derivatives (epalrestat, zopolrestat), spiro hydantoins (sorbinil), or spiro succinimides (minalrestat), have been mainly studied in relation to diabetic complications yet with poor clinical outcome. 26−28 At the present time, epalrestat is the sole ARI approved for clinical use but only in the Asian market.…”

Section: ■ Discussionmentioning

confidence: 99%

Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

et al. 2019

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Inhibition of aldose reductase (AR), the first enzyme of the polyol pathway, is a promising approach in treatment of diabetic complications. We proceeded with optimization of the thioxotriazinoindole scaffold of the novel AR inhibitor cemtirestat by replacement of sulfur with oxygen. A series of 2-(3-oxo-2H-[1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid derivatives (OTIs), designed by molecular modeling and docking, were synthesized. More electronegative and less bulky oxygen of OTIs compared to the sulfur of the original thioxotriazinoindole congeners was found to form a stronger Hbond with Leu300 of AR and to render larger rotational flexibility of the carboxymethyl pharmacophore. AR inhibitory activities of the novel compounds were characterized by the IC 50 values in a submicromolar range. Markedly enhanced inhibition selectivity relative to the structurally related aldehyde reductase was recorded. To conclude, structure modification of the original carboxymethylated thioxotriazinoindole cemtirestat by isosteric replacement of sulfur with oxygen in combination with variable N(2) simple substituents provided novel analogues with increased AR inhibition efficacy and markedly improved selectivity.

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“…Compounds 3b - f revealed higher inhibition efficacy in comparison with the clinically used epalrestat. Compound 3b is presently undergoing clinical evaluation under the name of setipiprant for treatment of androgenic alopecia [ 73 ]. On balance, these results establish the tetrahydropyridoindoles carboxymethylated at position 5 as a prospective scaffold for designing efficient AR inhibitors.…”

Section: Studies At the Level Of Isolated Enzymes And Free Radical Models In Vitro And In Silico: Sarmentioning

confidence: 99%

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

et al. 2021

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Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

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Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?

Cited by 8 publications

References 42 publications

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

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