Potent cyclic urea HIV protease inhibitors with 3-aminoindazole P2/P2' groups.
Cyclic ureas containing 3-aminoindazole P2/P2' groups are extremely potent inhibitors of HIV protease. The parent 3-aminoindazole 6 showed a Ki < 0.01 nM but poor translation of enzyme activity to antiviral activity was observed. A series of 3-alkylaminoindazoles revealed that translation improved with increasing lipophilicity. An X-ray crystal structure of 6 bound to HIV protease was obtained.
Rodgers
J D
JD
DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
Johnson
B L
BL
Wang
H
H
Erickson-Viitanen
S
S
Klabe
R M
RM
Bacheler
L
L
Cordova
B C
BC
Chang
C H
CH
D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D007202:Indicators and Reagents; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D007191:Indazoles; D007202:Indicators and Reagents; D014508:Urea; D016333:HIV Protease