Potent inhibitors of the HIV-1 protease with good oral bioavailabilities.
A series of novel pseudo-symmetrical and unsymmetrical inhibitors based on the backbone modification of a peptidomimetic were synthesized and found to be highly potent inhibitors of the HIV-1 protease (IC50 = 2.9 to < 0.5 nM). These compounds also possess good antiviral activity in vitro as measured by inhibition of the cytopathic effect of HIV-1(3B) in MT-4 lymphocytes. Importantly, some of these compounds also have good oral bioavailabilities in rats (F = 30.6% to 100%). One of these compounds 4C, also has good oral bioavailability in beagle dogs and cynomolgus monkeys.
Sham
H L
HL
Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Zhao
C
C
Marsh
K C
KC
Betebenner
D A
DA
Lin
S
S
McDonald
E
E
Vasavanonda
S
S
Wideburg
N
N
Saldivar
A
A
Robins
T
T
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D005260:Female; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D007202:Indicators and Reagents; D016333:HIV Protease