Linked Life Data

1901910

Source:http://linkedlifedata.com/resource/pubmed/id/1901910

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1991-5-21
pubmed:abstractText
A series of renin inhibitors with novel modifications at the P2 site has been prepared. Structure-activity relationships reveal that for a particular P2 fragment the in vitro potency is highly dependent on the nature of the P2' portion in addition to the P1-P1' group. The length of the P2 side chain and choice of epsilon-N P2 substitution have been found to be important for in vitro potency although the degree of unsaturation in the P2 side chain is not particularly significant. Molecular modeling studies have shown that it is possible for the P2 side chain to interact unfavorably with the P2' binding site. It has been possible to control the specificity for renin over cathepsin D by correct modification at the P2' and P1-P1' sites. Variations at the P4 site have been utilized to lower the log P values of these renin inhibitors while maintaining high potency. Compound 42, which exhibited an IC50 of 3.70 nM, log P of 2.3, and showed high specificity for renin, was selected for further studies. It was found to be very stable under neutral, acidic, and basic conditions. In simulated intestinal juice, compound 42 had a half-life of 37 min while it was virtually unaffected by simulated gastric juice after 4 h. Compound 42 produced a significant hypotensive response upon intravenous administration to the salt-depleted normotensive cynomolgus monkey.
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:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
N
pubmed:pagination
1258-71
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
New inhibitors of human renin that contain novel replacements at the P2 site.
pubmed:affiliation
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
pubmed:publicationType
Journal Article, Comparative Study