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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
1999-10-14
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pubmed:abstractText |
When the dialkylacetamide side chain of the ET(A)-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ET(B) over ET(A). By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ET(B) and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ET(B) receptor in modulating blood pressure; the observed hypertensive response to persistent ET(B) blockade is consistent with previous postulates and indicates that ET(B)-selective antagonists may not be suitable as agents for long-term systemic therapy.
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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 |
Sep
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AdlerAA,
pubmed-author:ChiouW JWJ,
pubmed-author:DixonD BDB,
pubmed-author:MarshK CKC,
pubmed-author:NguyenBB,
pubmed-author:OpgenorthT JTJ,
pubmed-author:SorensenB KBK,
pubmed-author:SzczepankiewiczB GBG,
pubmed-author:TaskerA SAS,
pubmed-author:WangLL,
pubmed-author:WessaleJ LJL,
pubmed-author:WinnMM,
pubmed-author:von GeldernT WTW
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3668-78
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pubmed:dateRevised |
2004-1-20
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pubmed:meshHeading |
pubmed-meshheading:10479298-Acetanilides,
pubmed-meshheading:10479298-Animals,
pubmed-meshheading:10479298-Blood Pressure,
pubmed-meshheading:10479298-Cell Line,
pubmed-meshheading:10479298-Endothelin-1,
pubmed-meshheading:10479298-Pyrrolidines,
pubmed-meshheading:10479298-Rats,
pubmed-meshheading:10479298-Rats, Sprague-Dawley,
pubmed-meshheading:10479298-Receptor, Endothelin B,
pubmed-meshheading:10479298-Receptors, Endothelin
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pubmed:year |
1999
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pubmed:articleTitle |
Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity.
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pubmed:affiliation |
Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. thomas.vongeldern@abbott.com
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pubmed:publicationType |
Journal Article
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