The design and synthesis of sulfonamides as caspase-1 inhibitors.
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Harter
William G
WG
Chemistry Department, Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA. william.harter@pfizer.com
Albrect
Hans
H
Brady
Kenneth
K
Caprathe
Bradley
B
Dunbar
James
J
Gilmore
John
J
Hays
Sheryl
S
Kostlan
Catherine R
CR
Lunney
Beth
B
Walker
Nigel
N
D001665:Binding Sites; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D015843:Serpins / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014764:Viral Proteins
D061945:Caspase Inhibitors; D015843:Serpins; D013449:Sulfonamides; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D020170:Caspase 1