Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.
Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.
Hungate
R W
RW
Merck Research Laboratories, West Point, PA 19486.
Chen
J L
JL
Starbuck
K E
KE
Vacca
J P
JP
McDaniel
S L
SL
Levin
R B
RB
Dorsey
B D
BD
Guare
J P
JP
Holloway
M K
MK
Whitter
W
W
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D007769:Lactams