Author/Authors :
Richard L. Mackman، نويسنده , , Adrian S. Ray، نويسنده , , Hon C. Hui، نويسنده , , Lijun Zhang، نويسنده , , Gabriel Birkus، نويسنده , , Constantine G. Boojamra، نويسنده , , Manoj C. Desai، نويسنده , , Janet L. Douglas، نويسنده , , Ying Gao، نويسنده , , Deborah Grant، نويسنده , , Geneviève Laflamme، نويسنده , , Kuei-Ying Lin، نويسنده , , David Y. Markevitch، نويسنده , , Ruchika Mishra، نويسنده , , Martin McDermott، نويسنده , , Rowchanak Pakdaman، نويسنده , , Oleg V. Petrakovsky، نويسنده , , Jennifer E. Vela، نويسنده , , Tomas Cihlar، نويسنده ,
Abstract :
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 (3 mg/kg) in Beagle dogs, high levels (>9.0 μM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate.
Keywords :
Nucleosides , HIV , Prodrugs , Cathepsin A , Phosphonates , Reverse transcriptase
