Linked Life Data

9554884

Source:http://linkedlifedata.com/resource/pubmed/id/9554884

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
1998-5-21
pubmed:abstractText
Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1513-23
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:9554884-Acetylene, pubmed-meshheading:9554884-Amino Acid Sequence, pubmed-meshheading:9554884-Animals, pubmed-meshheading:9554884-Aspartic Acid Endopeptidases, pubmed-meshheading:9554884-Blood Pressure, pubmed-meshheading:9554884-CHO Cells, pubmed-meshheading:9554884-Cricetinae, pubmed-meshheading:9554884-Drug Design, pubmed-meshheading:9554884-Endothelin-1, pubmed-meshheading:9554884-Enzyme Inhibitors, pubmed-meshheading:9554884-Humans, pubmed-meshheading:9554884-Male, pubmed-meshheading:9554884-Metalloendopeptidases, pubmed-meshheading:9554884-Molecular Sequence Data, pubmed-meshheading:9554884-Neprilysin, pubmed-meshheading:9554884-Phosphonic Acids, pubmed-meshheading:9554884-Rats, pubmed-meshheading:9554884-Rats, Sprague-Dawley, pubmed-meshheading:9554884-Recombinant Proteins, pubmed-meshheading:9554884-Structure-Activity Relationship
pubmed:year
1998
pubmed:articleTitle
Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.
pubmed:affiliation
Metabolic and Cardiovascular Diseases Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA.
pubmed:publicationType
Journal Article, Comparative Study