Synthesis and biological evaluation of prodrug-type anti-HIV agents: ester conjugates of carboxylic acid-containing dipeptide HIV protease inhibitors and a reverse transcriptase inhibitor.
On the basis of substrate transition-state mimic concept of HIV protease, a series of small-sized dipeptide inhibitors containing hydrophilic carboxyl group were designed and synthesized. These dipeptide inhibitors showed good HIV protease inhibitory activity, but their anti-HIV activity was poor. The low antiviral activities of these inhibitors were probably due to their inadequate cell membrane permeability caused by the presence of a free carboxylic acid in the inhibitors. Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, conjugates of HIV protease inhibitors with a nucleoside reverse transcriptase inhibitor were synthesized. Some of these conjugates exhibited excellent antiviral activity compared with that of individual inhibitors. The synergistic enhancement of anti-HIV activities of these conjugates may be due to their ability to penetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agents in the cytoplasm.
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Japan.
H
H
Matsumoto
T
T
Matsuda
S
S
Nakata
T
T
Mitoguchi
T
T
Kimura
Y
Y
Hayashi
Y
Y
Kiso
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002264:Carboxylic Acids; D003432:Cross-Linking Reagents; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004151:Dipeptides; D004355:Drug Stability; D004357:Drug Synergism; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D002264:Carboxylic Acids; D003432:Cross-Linking Reagents; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease