title: Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.
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.
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA. Richard.Mackman@gilead.com
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Hon C
authors.initials: HC
authors.lastname: Hui
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Boojamra
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
authors.forename: Janet L
authors.initials: JL
authors.lastname: Douglas
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Deborah
authors.initials: D
authors.lastname: Grant
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laflamme
authors.forename: Kuei-Ying
authors.initials: KY
authors.lastname: Lin
authors.forename: David Y
authors.initials: DY
authors.lastname: Markevitch
authors.forename: Ruchika
authors.initials: R
authors.lastname: Mishra
authors.forename: Martin
authors.initials: M
authors.lastname: McDermott
authors.forename: Rowchanak
authors.initials: R
authors.lastname: Pakdaman
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Petrakovsky
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Vela
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D004355:Drug Stability; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D009705:Nucleosides / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; C519972:GS-9131; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D006151:Guanosine; C527398:GS-9148; D000225:Adenine