1. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
- Author
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Mackman, Richard L., Ray, Adrian S., Hui, Hon C., Zhang, Lijun, Birkus, Gabriel, Boojamra, Constantine G., Desai, Manoj C., Douglas, Janet L., Gao, Ying, Grant, Deborah, Laflamme, Genevieve, Lin, Kuei-Ying, Markevitch, David Y., Mishra, Ruchika, McDermott, Martin, Pakdaman, Rowchanak, Petrakovsky, Oleg V., Vela, Jennifer E., and Cihlar, Tomas
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DRUG development , *DRUG design , *ENZYME inhibitors , *REVERSE transcriptase , *AMIDES , *PHOSPHONATES , *HIV , *PRODRUGS , *THERAPEUTICS - Abstract
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 (3mg/kg) in Beagle dogs, high levels (>9.0μM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. [Copyright &y& Elsevier]
- Published
- 2010
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