HIV-1 protease inhibitors: synthesis and biological evaluation of glycopeptidemimetics.
A series of glycopeptidemimetics based on the hydroxyethylene Phe-Phe isostere have been synthesized and evaluated for their ability to inhibit the enzyme HIV-1 protease. Incorporation of carbohydrate moieties at the P'2-position and elimination of P'3 amino acid in our lead compound 1, provided inhibitors with only nanomolar potencies (400-800 nM). However, incorporation of a carbohydrate moiety at the P'3-position with branched chain amino acid at the P'2-position, resulted in inhibitors with subnanomolar potencies. Within this series, compound 21 was the most potent inhibitor (IC50 value 0.17 nM). This compound has also shown to block the spread of HIV-1 in T-lymphoid cells at an inhibitor concentration of 200 nM.
Department of Medicinal Chemistry, Molecular Biology, Merck Research Laboratories, West Point, Pennsylvania 19486.
A K
AK
Ghosh
S P
SP
McKee
W M
WM
Sanders
P L
PL
Darke
J A
JA
Zugay
E A
EA
Emini
W A
WA
Schleif
J C
JC
Quintero
J R
JR
Huff
P S
PS
Anderson
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000382:microbiology
D006020:Glycopeptides; D017320:HIV Protease Inhibitors