Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor

Santin, José Roberto; Uchôa, Flávia De Toni; Lima, Maria do Carmo Alves de; Rabello, Marcelo Montenegro; Machado, Isabel Daufenback; Hernandes, Marcelo Zaldini; Amato, Angélica Amorim; Milton, Flora Aparecida; Webb, Paul; Neves, Francisco de Assis Rocha; Galdino, Suely Lins; Pitta, Ivan R.; Farsky, Sandra Helena Poliselli

doi:10.1016/j.ejps.2012.12.029

Cited by 18 publications

(35 citation statements)

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“…The data obtained in this study indicate that a new indole-thiazolidine called LYSO-7 is a PPAR and PPAR dual agonist and reduces the development of atherosclerotic plaques in LDLr -/-mice. Although a recent study suggests that LYSO-7 may be considered a PPAR-pan agonist [17], in our work, we observed only the activation of PPAR and PPAR transcription factors, whereas PPAR/ transactivation seemed unlikely under our experimental conditions. Atherosclerosis is recognized as a chronic inflammatory process resulting from the crosstalk of lipid metabolism and immune responses in the vasculature [26].…”

Section: Discussioncontrasting

confidence: 61%

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New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

César

Rudnicki

Heras

et al. 2015

Vascular Pharmacology

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Section: Discussioncontrasting

confidence: 61%

“…synthesized as previously described [17]. RSG, the anti-COX2 and anti-iNOS antibodies were Mouse antibodies against CD40 and CD40L were obtained from ABCAM (Cambridge, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

César

Rudnicki

Heras

et al. 2015

Vascular Pharmacology

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“…Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice. Many other authors have used similar approaches with promising outcomes (da Costa Leite et al, 2007;Barros et al, 2010;Araújo et al, 2011;Amato et al, DMD # 79012 5 2012;Santin et al, 2013a;Santin et al, 2013b;Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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Number of references: 55Number of words in the Abstract: 241 Number of words in the Introduction: 750Number of words in the Discussion: 828Nonstandard abbreviations: ADME, absorption, distribution, metabolism, and excretion; CL h , hepatic clearance; CL int , intrinsic clearance; ESI, electrospray ionization; GQ-11, 5-(indol-3-ylmethylene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione; HLM, human liver microsome; LC-HRMS, liquid chromatography coupled to high resolution mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple reaction monitoring; PPARγ, peroxisome proliferatoractivated receptor gamma; RLM, rat liver microsome; t 1/2 , half-life; TZD, thiazolidinedione;This article has not been copyedited and formatted. The final version may differ from this version. AbstractThiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

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“…Como já descrito anteriormente, nós mostramos que macrófagos de animais ANXA1 -/-apresentam concentrações menores de PPARγ, e que o aumento de sua expressão induzido pelo agonista PPAR pan (LYSO-7) em macrófagos de animais WT, não foi observado em macrófagos de animais ANXA1 -/- (Santin et al, 2013a). A Lyso-7 foi empregada neste estudo, uma vez que é o único agonista PPAR pan da classe das tiazolidinedionas, que atua sobre os 3 receptores e, ainda, é um inibidor da COX-2 (Santin et al, 2013a).…”

Section: Efeitos Da Anxa1 Sobre a Expressão Proteica De Pparγ Em Macrunclassified

“…A Lyso-7 foi empregada neste estudo, uma vez que é o único agonista PPAR pan da classe das tiazolidinedionas, que atua sobre os 3 receptores e, ainda, é um inibidor da COX-2 (Santin et al, 2013a). Nosso grupo de pesquisa tem se envolvido na caracterização do efeito anti-inflamatório desta molécula, mostrando que a administração oral desta inibe o desenvolvimento do lesão gástrica aguda, por inibir a migração de neutrófilos para a área lesada e a produção de NO pela ação da óxido nítrico induzível (Santin et al, 2013b).…”

Section: Efeitos Da Anxa1 Sobre a Expressão Proteica De Pparγ Em Macrunclassified

Controle da Anexina 1 sobre a expressão do receptor nuclear proliferador de peroxissomos em diferentes tipos celulares

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Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor

Cited by 18 publications

References 55 publications

New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

Controle da Anexina 1 sobre a expressão do receptor nuclear proliferador de peroxissomos em diferentes tipos celulares

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