Vascular and Cardiac Effects of Endothelin

Douglas, Stephen A.; Ohlstein, Eliot H.

doi:10.1007/978-3-642-56899-2_16

Cited by 5 publications

(2 citation statements)

References 343 publications

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“…Following experimental balloon injury there is neointima formation (17,18) associated with an induction of ET-1, ECE and endothelin receptor mRNA and protein expression. Administration of endothelin receptor antagonists and ECE inhibitors results in a reduction in neointima formation suggesting a role for ET-1 in the pathogenesis of restenosis (19). The relationship between ET-1 and induction of cell cycle regulatory molecules has only recently been explored (20).…”

Section: Endothelinmentioning

confidence: 99%

Cell cycle molecules and diseases of the cardiovascular system

et al. 2000

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Section: Endothelinmentioning

confidence: 99%

Cell cycle molecules and diseases of the cardiovascular system

et al. 2000

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“…In addition to a strong vasoconstriction, both receptors mediate long-term effects such as cell proliferation and fibrosis. As a consequence, the endothelins may have detrimental effects on angiogenesis, cardiac, and vascular remodeling, inflammation, and fibrosis. , A pathophysiological role is attributed to the endothelins, in particular to ET-1, in a number of renal, pulmonary, , cardiac, and vascular diseases , such as renal failure, , heart failure, , hypertension, , atherosclerosis, acute myocardial infarction, pulmonary arterial hypertension (PAH), and cerebral vasospasm . Accordingly, endothelin receptor antagonists are thought to offer a novel class of drugs to treat or even prevent such disorders. ,− …”

Section: Introductionmentioning

confidence: 99%

Novel Benzo[1,4]diazepin-2-one Derivatives as Endothelin Receptor Antagonists

et al. 2004

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Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.

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