Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.
Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.
Vara Prasad
J V
JV
Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48106, USA.
Markoski
L J
LJ
Boyer
F E
FE
Domagala
J M
JM
Ellsworth
E L
EL
Gajda
C
C
Hagen
S E
SE
Tait
B D
BD
Lunney
E A
EA
Tummino
P J
PJ
Ferguson
D
D
Holler
T
T
Hupe
D
D
Nouhan
C
C
Gracheck
S J
SJ
VanderRoest
S
S
Saunders
J
J
Iyer
K
K
Sinz
M
M
D000818:Animals; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology
D004220:Disulfides; D017320:HIV Protease Inhibitors; C400303:PD 178390; D011753:Pyrones; D013451:Sulfonic Acids; C005741:sulfamic acid