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rdf:type |
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lifeskim:mentions |
umls-concept:C0205177,
umls-concept:C0205314,
umls-concept:C0205531,
umls-concept:C0226896,
umls-concept:C0243072,
umls-concept:C0243076,
umls-concept:C0442027,
umls-concept:C0456387,
umls-concept:C0597357,
umls-concept:C0679622,
umls-concept:C1527415
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pubmed:issue |
5
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pubmed:dateCreated |
2001-5-31
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pubmed:abstractText |
In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0009-2363
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
606-12
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11383615-Animals,
pubmed-meshheading:11383615-Aorta, Thoracic,
pubmed-meshheading:11383615-Blood Pressure,
pubmed-meshheading:11383615-Decerebrate State,
pubmed-meshheading:11383615-Female,
pubmed-meshheading:11383615-Indicators and Reagents,
pubmed-meshheading:11383615-Magnetic Resonance Spectroscopy,
pubmed-meshheading:11383615-Male,
pubmed-meshheading:11383615-Muscle, Smooth, Vascular,
pubmed-meshheading:11383615-Muscle Contraction,
pubmed-meshheading:11383615-Pregnancy,
pubmed-meshheading:11383615-Rats,
pubmed-meshheading:11383615-Rats, Wistar,
pubmed-meshheading:11383615-Receptor, Endothelin A,
pubmed-meshheading:11383615-Receptor, Endothelin B,
pubmed-meshheading:11383615-Receptors, Endothelin,
pubmed-meshheading:11383615-Structure-Activity Relationship,
pubmed-meshheading:11383615-Sulfonamides
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pubmed:year |
2001
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pubmed:articleTitle |
Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.
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pubmed:affiliation |
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. haradah@yamanouchi.co.jp
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pubmed:publicationType |
Journal Article,
In Vitro
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