The discovery and structure—activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ETB receptor

Chan, Ming Fai; Kois, Adam; Verner, Erik; Raju, B.; Castillo, Rosario; Wu, Chia-Chien; Okun, Ilya; Stavros, Fiona; Balaji, V.

doi:10.1016/s0968-0896(98)80010-2

Cited by 30 publications

(14 citation statements)

References 32 publications

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“…1) has been reported as an antagonist of the human platelet thrombin receptor (PAR-1), 10 and other examples function as selective endothelin ET B receptor antagonists. 11 The most common synthetic approach for the construction of the isoxazole ring system involves the cycloaddition of alkynes to nitrile oxides. 2,3 A number of synthetic routes have been reported for the preparation of 5-aminoisoxazoles; these include condensation of esters with nitrile anions and then cyclization of the resulting b-ketonitriles with hydroxylamine, 12 addition of nitrile anions to a-chlorooximes, 13 condensation of a-bromo ketoximines with cyanide, 14 The most common synthetic methods reported for the preparation of 3-isoxazolecarboxamides involve amidation of the corresponding carboxylic acids 16 and cyclization of 2,4-dioxopentanamides with hydroxylamine.…”

Section: -(Alkylamino)-4-aryl-3-isoxazolecarboxamides Isocyanides Nimentioning

confidence: 99%

Reaction between isocyanides and nitrostyrenes in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides

Adib

Mahdavi

Malihi

et al. 2009

Tetrahedron Letters

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Section: -(Alkylamino)-4-aryl-3-isoxazolecarboxamides Isocyanides Nimentioning

confidence: 99%

Reaction between isocyanides and nitrostyrenes in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides

Adib

Mahdavi

Malihi

et al. 2009

Tetrahedron Letters

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“…The finding that the ET A receptor-selective antagonist BQ610, but not the ET B receptor-selective antagonist BQ788, decreased ET-1 induced MCP-1 expression implicates a role for the ET A receptor in ET-1-mediated inflammation [98]. Recently, it has been shown that aryl-alkane-sulfonamides and their derivatives may ameliorate ET-1-mediated inflammation [152,153] as well as an ET A selective N-(5-isoxazolyl) benzene-sulfonamide receptor antagonist that can be modified in the 4-position with aryl and substituted aryl groups to generate a ET B selective receptor antagonist [154,155].…”

Section: Cell Adhesion and Migrationmentioning

confidence: 99%

Recent Developments on Endothelin Antagonists as Immunomodulatory Drugs - from Infection to Transplantation Medicine

Nett¹,

Teixeira²,

Candinas³

et al. 2006

PRC

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Endothelin, a potent endogenous vasoconstrictor and mitogen that acts through the ET(A) and ET(B) receptors, has been not only implicated in the regulation of cardiovascular homeostasis but also in inflammatory responses, including that induced by infection and solid organ transplantation. Changes in capillary perfusion and leukocyte recruitment are important features of inflammation. The concentrations of ET are elevated in many forms of inflammation and are especially high in sepsis. The rise in plasma levels of ET during early stages of inflammation may initially have some positive homeostatic effects that might help to maintain vascular tone and blood pressure. However, high levels of ET compromise the appropriate matching of flow to tissue needs and contribute to the pathophysiology of microcirculatory derangements. Attempts at regulating the effects of ET by the use of pharmacological antagonists are complicated by important interactions between the ET(A) and ET(B) receptors. This review highlights findings of recent studies and patents in this area showing that the ET system, apart from being a marker of vascular and tissue injury, is directly involved in the pathophysiology of these disease processes as an immunomodulatory mediator.

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“…A sulfonamide group tethers the isoxazole and the thiophene moieties while an amide linkage connects the aryl group and the thiophene. They had already shown that isoxazoles with dimethyl substituents are preferred for binding affinity [70,81] and a halogen substitution on the 4-position increases the binding affinity by 3 to 5-fold [18,82]. They, therefore, synthesized [78,80] isoxazolylsulfonamides with chloro, bromo and methyl group at the 4-position of the isoxazole ring as in scheme 9.…”

Section: Chan Et Al ( I M M U N O P H a R M A C E U T I C S / T E X mentioning

confidence: 99%

“…Chan et al [82] reported the systematic modification of the ET A selective N -( 5 -isoxazolyl)benzenesulfonamide endothelin antagonists to 4-biphenyl and 5-aryl-2-thienylsulfonamide ET B selective antagonists, TBC-10894 (41) and TBC-10950 (42), respectively (Fig. (9)).…”

Section: Chan Et Al ( I M M U N O P H a R M A C E U T I C S / T E X mentioning

confidence: 99%

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Iqbal¹,

Sanghi²,

Das

2005

MRMC

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Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.

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The discovery and structure—activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ETB receptor

Cited by 30 publications

References 32 publications

Reaction between isocyanides and nitrostyrenes in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides

Reaction between isocyanides and nitrostyrenes in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides

Recent Developments on Endothelin Antagonists as Immunomodulatory Drugs - from Infection to Transplantation Medicine

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

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