Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor.
GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.
Boojamra
Constantine G
CG
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. DBoojamra@gilead.com
Mackman
Richard L
RL
Markevitch
David Y
DY
Prasad
Vidya
V
Ray
Adrian S
AS
Douglas
Janet
J
Grant
Deborah
D
Kim
Choung U
CU
Cihlar
Tomas
T
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D009705:Nucleosides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D006151:Guanosine; D005461:Fluorine; D015215:Zidovudine; D054303:HIV Reverse Transcriptase