Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.
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.
Mackman
Richard L
RL
Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA94404, USA. Richard.Mackman@gilead.com
Ray
Adrian S
AS
Hui
Hon C
HC
Zhang
Lijun
L
Birkus
Gabriel
G
Boojamra
Constantine G
CG
Desai
Manoj C
MC
Douglas
Janet L
JL
Gao
Ying
Y
Grant
Deborah
D
Laflamme
Genevieve
G
Lin
Kuei-Ying
KY
Markevitch
David Y
DY
Mishra
Ruchika
R
McDermott
Martin
M
Pakdaman
Rowchanak
R
Petrakovsky
Oleg V
OV
Vela
Jennifer E
JE
Cihlar
Tomas
T
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
D019380:Anti-HIV Agents; C519972:GS-9131; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D006151:Guanosine; C527398:GS-9148; D000225:Adenine