Endothelin-1 myocardial clearance and production and effect on capillary permeability in vivo

Dupuis, Jocelyn; Goresky, Carl A.; Rose, Colin P.; Stewart, Duncan J.; Cemacek, Peter

doi:10.1016/s0735-1097(96)82191-7

Cited by 3 publications

(2 citation statements)

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“…The potency of ET-1 is unequaled, with the exception of urotensin II (À log[EC 50 ] ¼ 9.5; Douglas et al, 2000). ET-1 elicits its effects through two receptors (http://www.iuphar.org/): ET A receptors, located in vascular smooth muscle cells (VSMC) and cardiomyocytes, mediate contraction, whereas ET B receptors, located on vascular endothelial cells (EC), mediate dilation and ET-1 uptake, and regulate ET-1 production (Arai et al, 1990;Barton & Yanagisawa, 2008;Brunner et al, 2006;Callera et al, 2007;Dupuis et al, 1997;Farhat et al, 2008;Komukai et al, 2010;Rubanyi & Polokoff, 1994;Sakurai et al, 1990;Sanchez et al, 2002). Additionally, ET B receptors can also be expressed on VSMC and elicit contractions (Sanchez et al, 2002;Teerlink et al, 1994).…”

Section: Cardiovascular Physiology Of Etmentioning

confidence: 99%

The Cardiovascular Physiology and Pharmacology of Endothelin-1

Thorin

Clozel

2010

Advances in Pharmacology

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One year after the discovery in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21 amino acids) peptide were quickly determined in humans and it was reported that in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then recognized as a likely mediator of pathological vasoconstriction in human. The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of bosentan, which entered clinical development in 1993, and was offered to patients with pulmonary arterial hypertension in 2001. In this report, we discuss the physiological and pathophysiological role of endothelium-derived ET-1, the pharmacology of its two receptors, focusing on the regulation of the vascular tone and as much as possible in humans. The coronary bed will be used as a running example, but references to the pulmonary, cerebral, and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of NO and ET-1, in which the implication of the ET(B) receptor may be central.

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Section: Cardiovascular Physiology Of Etmentioning

confidence: 99%

The Cardiovascular Physiology and Pharmacology of Endothelin-1

Thorin

Clozel

2010

Advances in Pharmacology

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“…9,10 ET B receptors are found also on endothelial cells where they clear ET-1 and mediate vasodilation through the release of NO and thromboxane. [12][13][14] The potentially wide application of endothelin antagonists has spurred intensive medicinal research and a number of chemical entities are being evaluated in the clinic. The first oral dual ET A /ET B antagonist bosentan has been approved for pulmonary arterial hypertension.…”

Section: Introductionmentioning

confidence: 99%

Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist

Wu¹,

Decker²,

Blok³

et al. 2004

J. Med. Chem.

103

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Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 0.08 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

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Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo

Dupuis

Schwab

Simard

et al. 1999

American Journal of Physiology-Gastrointestinal and Liver Physi

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Endothelin-1 (ET-1) is a 21-amino acid peptide produced by vascular endothelial cells that acts as a potent constrictor of hepatic sinusoids. Hepatic binding of tracer (125)I-labeled ET-1 was investigated in anesthetized dogs with the multiple-indicator dilution technique with simultaneous measurements of unlabeled immunoreactive ET-1 plasma levels. Despite 80% binding to albumin, tracer (125)I-ET-1 was avidly extracted by the liver, with only 15 +/- 6% of the peptide surviving passage through the organ. Exchange of ET-1 between plasma and binding sites, probably located on the surface of liver cells, was quantitatively described by a barrier-limited, space-distributed variable transit time model. Reversible and irreversible parallel binding sites were found. Reversible and irreversible plasma clearances of unbound (125)I-ET-1 were 0.084 +/- 0.033 ml. s(-1). g liver(-1) and 0.17 +/- 0.09 ml. s(-1). g liver(-1), respectively, and the dissociation rate constant for reversible binding was 0.24 +/- 0.12 s(-1). The specific ET(A) receptor antagonist BMS-182874 did not modify binding to either site. The nonspecific ET(A)/ET(B) antagonist LU-224332 dose-dependently reduced irreversible binding only. ET-1 levels in the hepatic vein were significantly lower than in the portal vein but were not different from those in the hepatic artery. The ratio between hepatic vein and portal vein levels (0.64 +/- 0.31) was considerably higher than survival fractions, suggesting a substantial simultaneous release of newly synthesized or stored ET-1 by the liver. These results demonstrate both substantial clearance and production of ET-1 by the intact liver. Hepatic ET-1 clearance is mediated by the ET(B) receptor, with the presence of reversible, nonspecific ET-1 binding at the liver surface

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Endothelin-1 myocardial clearance and production and effect on capillary permeability in vivo

Cited by 3 publications

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The Cardiovascular Physiology and Pharmacology of Endothelin-1

The Cardiovascular Physiology and Pharmacology of Endothelin-1

Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist

Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo

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Endothelin-1 myocardial clearance and production and effect on capillary permeability in vivo

Cited by 3 publications

References 0 publications

The Cardiovascular Physiology and Pharmacology of Endothelin-1

The Cardiovascular Physiology and Pharmacology of Endothelin-1

Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ETA Selective, and Orally Bioavailable Endothelin Antagonist

Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo

Contact Info

Product

Resources

About

Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist