Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors.
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.
Boojamra
Constantine G
CG
Gilead Science, Inc, Foster City, CA 94404, USA. dboojamra@gilead.com
Parrish
Jay P
JP
Sperandio
David
D
Gao
Ying
Y
Petrakovsky
Oleg V
OV
Lee
Sharon K
SK
Markevitch
David Y
DY
Vela
Jennifer E
JE
Laflamme
Genevieve
G
Chen
James M
JM
Ray
Adrian S
AS
Barron
Abraham C
AC
Sparacino
Mark L
ML
Desai
Manoj C
MC
Kim
Choung U
CU
Cihlar
Tomas
T
Mackman
Richard L
RL
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
D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase