Design of orally bioavailable, symmetry-based inhibitors of HIV protease.
A series of novel inhibitors of HIV-1 protease with excellent oral bioavailability is described. Differential acylation of the two amino groups of symmetry-based diamine core groups 2-5 led to unsymmetrically substituted inhibitors 17-43, many of which inhibited HIV protease at subnanomolar concentrations. Anti-HIV activity in vitro was observed at 0.1-1 microM. A systematic evaluation of the pharmacokinetic behavior of these inhibitors in rats identified the influence of aqueous solubility, molecular size and hydrogen-bonding functionality. Compound 30 (A-80987) was selected for further evaluation based on a favorable Cmax/ ED50 ratio (> 20) and half-life (> 2 h).
Kempf
D J
DJ
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064.
Marsh
K C
KC
Fino
L C
LC
Bryant
P
P
Craig-Kennard
A
A
Sham
H L
HL
Zhao
C
C
Vasavanonda
S
S
Kohlbrenner
W E
WE
Wideburg
N E
NE
D000284:Administration, Oral; D000595:Amino Acid Sequence; D001682:Biological Availability; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors