Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.
Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.
Skulnick
H I
HI
Discovery Chemistry Research, Pharmacia and Upjohn, Kalamazoo, Michigan 49001, USA.
Johnson
P D
PD
Aristoff
P A
PA
Morris
J K
JK
Lovasz
K D
KD
Howe
W J
WJ
Watenpaugh
K D
KD
Janakiraman
M N
MN
Anderson
D J
DJ
Reischer
R J
RJ
Schwartz
T M
TM
Banitt
L S
LS
Tomich
P K
PK
Lynn
J C
JC
Horng
M M
MM
Chong
K T
KT
Hinshaw
R R
RR
Dolak
L A
LA
Seest
E P
EP
Schwende
F J
FJ
Rush
B D
BD
Howard
G M
GM
Toth
L N
LN
Wilkinson
K R
KR
Romines
K R
KR
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
D017320:HIV Protease Inhibitors; D011753:Pyrones; D013449:Sulfonamides