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rdf:type |
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lifeskim:mentions |
umls-concept:C0178499,
umls-concept:C0205177,
umls-concept:C0205314,
umls-concept:C0205531,
umls-concept:C0226896,
umls-concept:C0243076,
umls-concept:C0441513,
umls-concept:C0442027,
umls-concept:C0456387,
umls-concept:C0679622,
umls-concept:C0914912,
umls-concept:C1527177,
umls-concept:C1527178,
umls-concept:C1527415
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pubmed:issue |
4
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pubmed:dateCreated |
1998-3-17
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pubmed:abstractText |
A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-a]pyridine derivative 2. The unique screening lead (2) was discovered by a two-step intentional random screening process, involving recognition of the relationship between BK and angiotensin II (Ang II) and the common structural features. Systematic chemical modification of 2 elucidated the structural requirements essential for B2 binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo- 2- methylimidazo[1,2-a]pyridine skeleton as the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2,6-dichlorobenzene ring to allow these compounds to adopt the characteristic active conformation. The representative lead compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors, with nanomolar IC50S and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at an oral dose of 1 mg/kg. Pharmacokinetic studies of compounds 47c and 50b in rats highlighted their excellent oral bioavailabilities, indicating that they represent the first orally active non-peptide B2 antagonists reported to date.
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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 |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AbeYY,
pubmed-author:AsanoMM,
pubmed-author:HatoriCC,
pubmed-author:ImaiKK,
pubmed-author:InamuraNN,
pubmed-author:InoueTT,
pubmed-author:KatayamaAA,
pubmed-author:KayakiriHH,
pubmed-author:OkaHH,
pubmed-author:SatohSS,
pubmed-author:SawadaYY,
pubmed-author:TanakaHH
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pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
564-78
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pubmed:dateRevised |
2003-11-14
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pubmed:meshHeading |
pubmed-meshheading:9484506-Administration, Oral,
pubmed-meshheading:9484506-Angiotensin II,
pubmed-meshheading:9484506-Animals,
pubmed-meshheading:9484506-Biological Availability,
pubmed-meshheading:9484506-Bradykinin,
pubmed-meshheading:9484506-Bronchodilator Agents,
pubmed-meshheading:9484506-Drug Design,
pubmed-meshheading:9484506-Guinea Pigs,
pubmed-meshheading:9484506-Ileum,
pubmed-meshheading:9484506-Imidazoles,
pubmed-meshheading:9484506-Indicators and Reagents,
pubmed-meshheading:9484506-Male,
pubmed-meshheading:9484506-Models, Molecular,
pubmed-meshheading:9484506-Molecular Conformation,
pubmed-meshheading:9484506-Molecular Structure,
pubmed-meshheading:9484506-Muscle, Smooth,
pubmed-meshheading:9484506-Pyridines,
pubmed-meshheading:9484506-Rats,
pubmed-meshheading:9484506-Rats, Sprague-Dawley,
pubmed-meshheading:9484506-Receptor, Bradykinin B2,
pubmed-meshheading:9484506-Receptors, Bradykinin,
pubmed-meshheading:9484506-Structure-Activity Relationship,
pubmed-meshheading:9484506-Vasoconstriction
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pubmed:year |
1998
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pubmed:articleTitle |
A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework.
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pubmed:affiliation |
Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
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pubmed:publicationType |
Journal Article
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