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

Richard L. Mackman, 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

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosph onic 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.

Original languageEnglish (US)
Pages (from-to)3606-3617
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number10
DOIs
StatePublished - May 15 2010

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Keywords

  • Cathepsin A
  • HIV
  • Nucleosides
  • Phosphonates
  • Prodrugs
  • Reverse transcriptase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Mackman, R. L., Ray, A. S., Hui, H. C., Zhang, L., Birkus, G., Boojamra, C. G., Desai, M. C., Douglas, J. L., Gao, Y., Grant, D., Laflamme, G., Lin, K. Y., Markevitch, D. Y., Mishra, R., McDermott, M., Pakdaman, R., Petrakovsky, O. V., Vela, J. E., & Cihlar, T. (2010). Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorganic and Medicinal Chemistry, 18(10), 3606-3617. https://doi.org/10.1016/j.bmc.2010.03.041