title: Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. DBoojamra@gilead.com
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Boojamra
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.forename: David Y
authors.initials: DY
authors.lastname: Markevitch
authors.forename: Vidya
authors.initials: V
authors.lastname: Prasad
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Janet
authors.initials: J
authors.lastname: Douglas
authors.forename: Deborah
authors.initials: D
authors.lastname: Grant
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: 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
chemical_list: 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