New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors

Cimetiere, B.; Dubuffet, Thierry; Landras, C.; Descombes, Jean-Jacques; Simonet, Serge; Verbeuren, Tony J.; Lavielle, Gilbert

doi:10.1016/s0960-894x(98)00221-2

Cited by 22 publications

(10 citation statements)

References 10 publications

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“…One TP receptor antagonist still in development is S18886 (terutroban) [71]. S18886 was discovered as a lead compound during screening of different polysubstituted analogs of tetrahydronaphthalene [75,76]. Several potent TP antagonists comprised of a carboxylic acid and a benzenesulfonamide group separated by a spacer had previously been characterized.…”

Section: Thromboxane Receptor Antagonistsmentioning

confidence: 99%

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Dowal¹,

Flaumenhaft

2010

CVP

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Platelets are key mediators of thrombosis. Drugs that interfere with platelet activation substantially improve survival in arterial thrombotic disease. One attractive family of drug targets which has already been exploited in the development of antiplatelet agents are G-protein coupled receptors (GPCRs). Yet limitations of present antiplatelet agents, including incomplete efficacy, bleeding and drug resistance, have spurred the development of new drugs directed at alternative platelet GPCRs. Compounds that target platelet receptors including P2Y(12), protease-activated receptor-1 (PAR1), the thromboxane A(2) receptor (TP receptor), the prostaglandin receptor (EP3 receptor), and the serotonin receptor (5-HT(2A) receptor) have been identified and are in various phases of clinical development and use. Yet, improving the clinical profile of reagents targeting platelet GPCRs may not be only a matter of blocking alternative GPCRs. A more detailed understanding of GPCR function is leading to the development of pharmacophores with novel mechanisms of drug action. Identifying compounds that work by alternative mechanisms may be equally or more valuable than developing reagents targeting different GPCRs. Pharmacological concepts such as GPCR oligomerization, allosterism, and targeting GPCR-G protein interactions may ultimately provide opportunities to more effectively control platelet activation in the clinical setting. In this review, we will discuss the utility and limitations of GPCR-targeted antiplatelet therapies in clinical use and development. We will also consider emerging concepts in GPCR pharmacology that have the potential to foster the development of GPCR-targeted reagents with novel mechanisms of action and improved clinical profiles.

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Section: Thromboxane Receptor Antagonistsmentioning

confidence: 99%

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Dowal¹,

Flaumenhaft

2010

CVP

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“…The pharmacological experiments showed that G004 had a larger capacity than glimepiride to increase insulin secretion in vivo and in vitro experiments (Wu et al ., ; Yang and Wu, ). In addition, it reduced the triglyceride, the free fatty acid levels in k‐kay mice and had an an excellent property to reduce collagen–epinephrine‐induced mouse mortality (Cimetiere et al ., ; Audoly et al ., ; Zhang et al ., ; Wu et al ., ; Shang et al ., ). All these pharmacological properties favor G004 as a promising novel sulfonylurea hypoglycemic agent, which aims at reducing vascular complications as well as controlling glucose excursion for type II diabetes.…”

Section: Introductionmentioning

confidence: 99%

Gradient elution mode for the troubleshooting of matrix effect on the determination of G004 in different tissues by LC‐MS/MS

Agbokponto

Ding

et al. 2014

Biomedical Chromatography

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A steep gradient elution mode was applied to reduce the risk of matrix effect (ME) for the determination of G004, a novel sulfonylurea hypoglycemic drug, in a tissue distribution study by LC-MS/MS. The mass spectra of the total-ion-current chromatograms combined with the post-column infusion traces enabled the 'unseen' interfering species to be directly detected, and ensured that the chromatography conditions and sample preparation method were adequate to overcome the ME. According to this, a steep gradient elution mode was designed to overcome the intense ME from different tissues. The analysis was performed by monitoring the transitions m/z 558.1 → 419.0 for G004 and m/z 489.3 → 364.1 for glimepiride used as the internal standard. Calibration curves recovered over a range from 0.1 to 10000 ng/mL for seven different tissues. Sex-related difference was found in the tissue distribution. The drug levels in the tissues of female rats were about two to three times higher than those in male counterparts. The highest level was observed in liver, then in kidney, heart, pancreas, lung and spleen, but no G004 was detected in brain. G004 was slowly eliminated from female rats compared with male rats. There was no long-term accumulation of G004 in male or female rat tissues.

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“…However, treatment with thromboxane synthase inhibitors may be followed by a rise of PGH 2 in platelets, favoring a pro-aggregatory activity (19). S18886, a polysubstituted tetrahydronaphthalene deriv-ative, is a new and highly selective TPr antagonist with a long duration of action (20,21). It exerts potent antiplatelet and antivasoconstrictory effects via the TPr and antagonizes the actions of TxA 2 , as well as of other arachidonic acid products (prostaglandin PGH 2 , PGF 2 ␣, HETE acids, and isoprostanes) (9).…”

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confidence: 99%

Renal Effects of S18886 (Terutroban), a TP Receptor Antagonist, in an Experimental Model of Type 2 Diabetes

et al. 2007

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Thromboxane A 2 (TxA 2 ) is assumed to contribute to the development of diabetes complications, including nephropathy. We investigated whether the selective thromboxaneprostanoid endoperoxide receptor antagonist, S18886, ameliorates renal damage in uninephrectomized (UNX) obese Zucker rats (OZR). S18886, at doses of 10 (S18886-10) and 30 (S18886-30) mg ⅐ kg ؊1 ⅐ day ؊1 , was administered to UNX-OZR by gavage over 8 weeks (n ‫؍‬ 8 each group). UNX lean rats (n ‫؍‬ 12) and OZR rats that received placebo (OZR-PLAC, n ‫؍‬ 8) served as controls. As compared with the OZR-PLAC, S18886 had no significant effect on the elevated blood pressure and the enhanced creatinine clearance, while augmented proteinuria was partially prevented (؊12 and ؊37%, low and high dose, respectively; NS). The increased excretion of transforming growth factor ␤ 1 (TGF-␤ 1 ) and of the thromboxane metabolite 2,3-dinor thromboxane B 2 (TxB 2 ) was lowered (P < 0.05). S18886 prevented both the enhanced mesangiolysis (P < 0.01) in the OZR-PLAC as well as enlargement and degeneration of podocytes. In the blood, S18886-30 augmented the antioxidant enzymes (P < 0.01) and lessened the increase of plasma advanced oxidation protein products (؊25%, NS). Body weight, hyperglycemia, and dyslipidemia remained uninfluenced under both doses of treatment. S18886 has renoprotective properties in the model of UNX-OZR. It prevents mesangiolysis, reduces urinary TGF-␤ 1 and 2,3-dinor-TxB 2 excretion, and enhances the antioxidative defense. Diabetes 56:968 -974, 2007

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New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors

Cited by 22 publications

References 10 publications

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Gradient elution mode for the troubleshooting of matrix effect on the determination of G004 in different tissues by LC‐MS/MS

Renal Effects of S18886 (Terutroban), a TP Receptor Antagonist, in an Experimental Model of Type 2 Diabetes

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