Synthesis, anti-HIV activity, and resistance profiles of ribose modified nucleoside phosphonates.
A series of nucleoside phosphonate reverse transcriptase (RT) inhibitors have been synthesized and their anti-HIV activity and resistance profiles evaluated. The most potent analog [5-(6-amino-purin-9-yl)-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (d4AP) demonstrated a HIV EC(50)=2.1 microM, and the most favorable resistance profile against HIV-1 variants with K65R, M184V or multiple thymidine analog mutations in RT.
Mackman
Richard L
RL
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. rmackman@gilead.com
Boojamra
Constantine G
CG
Prasad
Vidya
V
Zhang
Lijun
L
Lin
Kuei-Ying
KY
Petrakovsky
Oleg
O
Babusis
Darius
D
Chen
James
J
Douglas
Janet
J
Grant
Deborah
D
Hui
Hon C
HC
Kim
Choung U
CU
Markevitch
David Y
DY
Vela
Jennifer
J
Ray
Adrian
A
Cihlar
Tomas
T
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006678:HIV / Q000187:drug effects* / Q000235:genetics*; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000068698:Tenofovir
C526695:(5-(6-amino-purin-9-yl)-2,5-dihydrofuran-2-yloxymethyl)phosphonic acid; D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine