title: Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors.
abstract: A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.
authors.affiliation: Gilead Science, Inc, Foster City, CA 94404, USA. dboojamra@gilead.com
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Boojamra
authors.forename: Jay P
authors.initials: JP
authors.lastname: Parrish
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Petrakovsky
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Lee
authors.forename: David Y
authors.initials: DY
authors.lastname: Markevitch
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Vela
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laflamme
authors.forename: James M
authors.initials: JM
authors.lastname: Chen
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Abraham C
authors.initials: AC
authors.lastname: Barron
authors.forename: Mark L
authors.initials: ML
authors.lastname: Sparacino
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase