Structure-based design of caspase-1 inhibitor containing a diphenyl ether sulfonamide.
A series of compounds was designed and prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase-1. These inhibitors, which employ a diphenyl ether sulfonamide, were designed to improve potency by forming favorable interactions between the diphenyl ether rings and the prime side hydrophobic region. An X-ray crystal structure of a representative member of the diphenyl ether sulfonamide series bound to the active site of caspase-1 was obtained.
Shahripour
A B
AB
Department of Chemistry, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. shahipour@pfizer.com
Plummer
M S
MS
Lunney
E A
EA
Sawyer
T K
TK
Stankovic
C J
CJ
Connolly
M K
MK
Rubin
J R
JR
Walker
N P
NP
Brady
K D
KD
Allen
H J
HJ
Talanian
R V
RV
Wong
W W
WW
Humblet
C
C
D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D004987:Ethers; D013449:Sulfonamides; C440391:diphenyl ether sulfonamide; D020170:Caspase 1