2. Academic Validation
  3. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

  • Bioorg Med Chem. 2010 May 15;18(10):3606-17. doi: 10.1016/j.bmc.2010.03.041.
Richard L Mackman 1,  Adrian S Ray,  Hon C Hui,  Lijun Zhang,  Gabriel Birkus,  Constantine G Boojamra,  Manoj C Desai,  Janet L Douglas,  Ying Gao,  Deborah Grant,  Genevieve Laflamme,  Kuei-Ying Lin,  David Y Markevitch,  Ruchika Mishra,  Martin McDermott,  Rowchanak Pakdaman,  Oleg V Petrakovsky,  Jennifer E Vela,  Tomas Cihlar
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA. Richard.Mackman@gilead.com
PMID: 20409721 DOI: 10.1016/j.bmc.2010.03.041
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 (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate.

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