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S 19812 (N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl) butan- amide, CAS 181308-68-9), a dual inhibitor of cyclooxygenase and lipoxygenase pathways, was evaluated in different models of pain and inflammation. Its gastric tolerance was also investigated. After acute oral treatment S 19812 exhibited a non-opioid analgesic activity observed in the phenylbenzoquinone-in-duced writhing model in mice (El[sub50] = 2.1 mg/kg) and in the carrageenan-in-duced hyperalgesia model in rats (ED[sub50 = 9.1 mg/kg, preventive treatment; 8.3 mg/ kg, curailve treatment). Anti-inflammatory activity was observed in the adjuvant-induced arthritis in rat (inhibition of edema ED[sub50] = 11 mg/kg/day p.o., day 28). In rats and mice, S 19812 exhibited an excellent gastric tolerance at doses up to 800 mg/kg p.o. [ABSTRACT FROM AUTHOR]

Investigates the general synthetic pathway and the interactions with arachidonic acid metabolism of hydroxy-N-methyl 4-(2,3-bis-(4-methoxy-phenyl)-thiophen-5-yl)butanamide. Dual inhibition of cyclooxygenase and 5-lipoxygenase pathways in vitro in rat polymorphonuclear neutrophils and ex vivo in mice blood; Melting points; Pharmacology.

The binding profile of [3H]BHDP ([3H]N-benzyl-N′-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine) was evaluated. [3H]BHDP labelled a single class of binding sites with high affinity (Kd=2–3 nM) in rat liver mitochondria and synaptic membranes. The pharmacological characterization of these sites using σ reference compounds revealed that these sites are σ receptors and, more particularly, σ1 receptors. Indeed, BHDP inhibited [3H]pentazocine binding, a marker for σ1 receptors, with high affinity in a competitive manner. BHDP is selective for σ1 receptors since it did not show any relevant affinity for most of the other receptors, ion channels or transporters tested. Moreover, in an in vitro model of cellular hypoxia, BHDP prevented the fall in adenosine triphosphate (ATP) levels caused by 24 h hypoxia in cultured astrocytes. Taken together, these results demonstrate that [3H]BHDP is a potent and selective ligand for σ1 receptors showing cytoprotective effects in astrocytes. [Copyright &y& Elsevier]

Sterol regulatory element binding protein (SREBP) is a key lipogenic transcription factor that has been implicated in the pathogenesis of dyslipidemia. We previously demonstrated that high glucose and streptozotocin (STZ)-induced type 1 diabetes decrease AMPK activity and cause lipid accumulation both in HepG2 hepatocytes in vitro, and in mouse liver in vivo, associated with hyperlipidemia. These changes were prevented by metformin or a synthetic polyphenol, S17834. We have further investigated the role of S 17834 in regulating SREBP and lipid metabolism. In STZ-induced diabetic mice, the nuclear active form (∼68 kDa) of liver SREBP-1 was increased 5-fold, and the increase was significantly prevented by S17834 (130 mg/kg/day), suggesting that the lipid-lowering effect of S17834 is associated with suppression of SREBP-1. Exposure of HepG2 cells to high glucose in culture resulted in increased expression of the precursor and nuclear active form of SREBP-1, as well as enhanced nuclear translocation of SREBP- 1 as detected by immunofluorescent staining. An increase in the SREBP-1 target enzyme, fatty acid synthase (FAS), was associated with an increase in hepatocellular triglyceride accumulation. In contrast, S17834 (l0 micro;M) or metformin (2 mM) significantly increased AMPK activity and inhibited activation of SREBP and induction of FAS, and thereby lowered hepatocellular triglyceride levels. Moreover, the ability of S17834 to downregulate SREBP-1 and FAS is mimicked by overexpression of the constitutively active AMPK, and largely prevented by a dominant-negative AMPK. These results indicate that polyphenols attenuate hepatic lipid accumulation associated with high glucose via inhibition of de novo fatty acid synthesis via activation of AMPK and suppression of SREBP-1, and point to new approaches using small molecules for treating dyslipidemia associated with diabetes. [ABSTRACT FROM AUTHOR]

Our recent studies show that the synthetic polyphenol, S 17834, stimulates AMP-activated protein kinase (AMPK) more potently than resveratrol or metformin. Stimulation of AMPK by S17834 was shown to attenuate high glucose-induced lipid accumulation in HepG2 cells, as well as to be associated with a reduction in hepatic and serum lipids, and atherosclerosis in type 1 diabetic LDL receptor deficient (LDLR-/-) mice. To determine the effect of S17834 in obesity-induced insulin resistance and type 2 diabetes, LDLR-/- mice were fed a high fat, high sucrose (HFHS) diet for 16 weeks. Compared with normal chow, body weight gain increased ∼3-fold, and insulin resistance index, as determined by the homeostasis model assessment for insulin resistance (HOMAIR), was increased ∼2.5-fold. Hepatic steatosis caused by the HFHS diet was accompanied in the liver by decreased phosphorylation of AMPK and the AMPK downstream effector, acetyl CoA carboxylase (ACC) compared with chow fed mice. The HFHS diet caused a ∼2-fold increase in plasma cholesterol levels as well as a 4-fold increase in oil red O stained atherosclerotic lesions in aortic mot cross sections. S17834 administration (130 mg/kg/day, 16 weeks) significantly protected mice against diet-induced obesity and systemic insulin resistance. Treatment with S 17834 was accompanied by increased AMPK and ACC phosphorylation in the liver and improvement in hepatic steatosis. S17834 also significantly decreased plasma cholesterol levels and attenuated the development of aortic atherosclerotic lesions. These data show that protection afforded by S17834 from the exaggerated hyperlipidemia and vascular disease caused by type 1 diabetes extends to type 2 diabetes in LDLR-/- mice. Improvements in body weight, insulin resistance, hepatic steatosis, hyperlipidemia, and atherosclerosis may be attributed to the ability of the polyphenol to stimulate AMPK as demonstrated here to occur in the mouse liver. Activation of AMPK by polyphenols, like S17834, represents a major new avenue for treatment of hyperlipidemia and vascular disease in both type 1 and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sirt1 is one of seven mammalian homologs of Sir2, an NAD-dependent deacetylase that functions as a novel metabolic sensor connecting aging and metabolism. We recently discovered that polyphenols stimulate AMPK activity and lower hepatic lipids, contributing to their beneficial effects on accelerated hyperlipidemia and atherosclerosis in diabetes. Here we examined if Sirt1 mediates the effect of polyphenols on AMPK and its lipid metabolic effects. The in vitro Fluor de Lys deacetylation assay showed that Sirt1 catalytic activity was significantly increased by polyphenols including resveratrol and a synthetic polyphenol, S17834, and decreased by Sirt1 inhibitors, nicotinamide and suramin, respectively. The two polyphenolic Sirt1 activators substantially stimulated phosphorylation of AMPK and its downstream effector, acetyl CoA carboxylase, in cultured human HepG2 hepatocytes and HEK293 cells, but not in HeLa cells deficient in LKB1. These responses were largely blocked by inhibition of Sirt1 deacetylation with nicotinamide or splitomicin. Importantly, downregulation of Sirt1 using lentivirus-mediated Sirt1 shRNA completely abolished the basal and polyphenol-induced AMPK activation. Furthermore, studies with a dominant negative Sirt1 (Sirt1H355A) and Sirt1 inhibitors revealed that the effects of polyphenols on hepatocellular AMPK signaling and lipids depend on Sirt1 activity in a HepG2 cell model of high glucose-induced lipid accumulation. Overexpression of wild type Sirt1 also stimulated AMPK, which was inhibited by high glucose, as well as reduced triglyceride levels that were enhanced by high glucose. The effects of wild type Sirtl were completely blocked by a dominant negative AMPK (AMP-Ka1phaK45R). These results implicate Sirt1 stimulation of AMPK as a key regulator of lipid metabolism in bepatocytes. Because of the associated improvements seen in hyperlipidemia and atherosclerosis caused by polyphenols in type 1 and type 2 mouse models, these data suggest that Sirt1 and AMPK may be attractive therapeutic targets for diabetes. [ABSTRACT FROM AUTHOR]

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser428, and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKβ, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/ AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases. [ABSTRACT FROM AUTHOR]

The general synthetic pathway and the interactions with arachidonic acid metabolism of the new compound S 19812 (N-hydroxy-N-methyl 4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)butanamide, CAS 181308-68-9) were investigated. S 19812 was selected for its well balanced dual inhibition of cyclooxygenase and 5-lipoxygenase pathways in vitro in rat polymorphonuclear neutrophils (PMNs) (IC50 PGE2: 0.10 mumol/l, LTB4: 0.07 mumol/l) and ex vivo in mice blood (ED50 PGE2: 13.1 mg/kg, LTB4: 20.8 mg/kg). These properties make this drug a promising therapeutic agent for pain and inflammation associated with osteoarthritis.

S 19812 (N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl) butanamide, CAS 181308-68-9), a dual inhibitor of cyclooxygenase and lipoxygenase pathways, was evaluated in different models of pain and inflammation. Its gastric tolerance was also investigated. After acute oral treatment S 19812 exhibited a non-opioid analgesic activity observed in the phenylbenzoquinone-induced writhing model in mice (ED50 = 2.1 mg/kg) and in the carrageenan-induced hyperalgesia model in rats (ED50 = 9.1 mg/kg, preventive treatment; 8.3 mg/kg, curative treatment). Anti-inflammatory activity was observed in the adjuvant-induced arthritis in rat (inhibition of edema ED50 = 11 mg/kg/day p.o., day 28). In rats and mice, S 19812 exhibited an excellent gastric tolerance at doses up to 800 mg/kg p.o.