|
rdf:type |
|
|
lifeskim:mentions |
umls-concept:C0028621,
umls-concept:C0033262,
umls-concept:C0205314,
umls-concept:C0220781,
umls-concept:C0260127,
umls-concept:C0679622,
umls-concept:C0718463,
umls-concept:C1707689,
umls-concept:C1880355,
umls-concept:C1883254,
umls-concept:C1955880,
umls-concept:C1957245,
umls-concept:C1999216,
umls-concept:C2352228,
umls-concept:C2698650
|
|
pubmed:issue |
10
|
|
pubmed:dateCreated |
2010-5-12
|
|
pubmed:abstractText |
GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3mg/kg) in Beagle dogs, high levels (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
May
|
|
pubmed:issn |
1464-3391
|
|
pubmed:author |
pubmed-author:BirkusGabrielG,
pubmed-author:BoojamraConstantine GCG,
pubmed-author:CihlarTomasT,
pubmed-author:DesaiManoj CMC,
pubmed-author:DouglasJanet LJL,
pubmed-author:GaoYingY,
pubmed-author:GrantDeborahD,
pubmed-author:HuiHon CHC,
pubmed-author:LaflammeGenevieveG,
pubmed-author:LinKuei-YingKY,
pubmed-author:MackmanRichard LRL,
pubmed-author:MarkevitchDavid YDY,
pubmed-author:McDermottMartinM,
pubmed-author:MishraRuchikaR,
pubmed-author:PakdamanRowchanakR,
pubmed-author:PetrakovskyOleg VOV,
pubmed-author:RayAdrian SAS,
pubmed-author:VelaJennifer EJE,
pubmed-author:ZhangLijunL
|
|
pubmed:copyrightInfo |
Copyright 2010 Elsevier Ltd. All rights reserved.
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
15
|
|
pubmed:volume |
18
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
3606-17
|
|
pubmed:meshHeading |
pubmed-meshheading:20409721-Adenine,
pubmed-meshheading:20409721-Animals,
pubmed-meshheading:20409721-Anti-HIV Agents,
pubmed-meshheading:20409721-CD4-Positive T-Lymphocytes,
pubmed-meshheading:20409721-Dogs,
pubmed-meshheading:20409721-Drug Design,
pubmed-meshheading:20409721-Drug Resistance, Viral,
pubmed-meshheading:20409721-Drug Stability,
pubmed-meshheading:20409721-Guanosine,
pubmed-meshheading:20409721-HIV-1,
pubmed-meshheading:20409721-Nucleosides,
pubmed-meshheading:20409721-Phosphonic Acids,
pubmed-meshheading:20409721-Prodrugs,
pubmed-meshheading:20409721-Reverse Transcriptase Inhibitors,
pubmed-meshheading:20409721-Tumor Cells, Cultured
|
|
pubmed:year |
2010
|
|
pubmed:articleTitle |
Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.
|
|
pubmed:affiliation |
Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA. Richard.Mackman@gilead.com
|
|
pubmed:publicationType |
Journal Article
|
