Linked Life Data

9888839

Source:http://linkedlifedata.com/resource/pubmed/id/9888839

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1999-2-11
pubmed:abstractText
The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of Ki to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
14
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
135-52
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors.
pubmed:affiliation
DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0500, USA. George.V.DeLucca@dupontpharma.com
pubmed:publicationType
Journal Article