Linked Life Data

7685996

Source:http://linkedlifedata.com/resource/pubmed/id/7685996

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1993-7-22
pubmed:abstractText
Pyridinone derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and HIV-1 replication in cell culture. However, the potential clinical usefulness of these compounds as monotherapeutic agents may be limited by the selection of inhibitor-resistant viral variants. Resistance in cell culture is due primarily to mutational alterations at RT amino acid residues 103 and 181. A recombinant HIV-1 RT containing both of these mutations was used to screen a panel of pyridinone analogs for inhibitory activity. L-696,229 and L-697,661, pyridinones currently undergoing clinical evaluation, were more than 4,000-fold weaker against the mutant enzyme than against the wild-type enzyme. In contrast, one derivative of L-696,229, L-702,019 (3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyrid in-2(1H)-thione), showed only three-fold different potencies against the two enzymes. L-702,019 was also a potent inhibitor of the replication of mutant HIV-1 containing the individual mutations at amino acid 103 or 181 as well as of clinical isolates resistant to L-697,661 and L-696,229. Isolation and analysis of resistant viral variants in cell culture showed that significant resistance to L-702,019 could be engendered only by multiple amino acid substitutions in RT. Accordingly, these studies demonstrated the potential of identifying second-generation specific HIV-1 RT inhibitors that can overcome the viral resistance selected by the first generation of inhibitors.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0066-4804
pubmed:author
pubmed:issnType
Print
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
947-9
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors.
pubmed:affiliation
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486.
pubmed:publicationType
Journal Article