Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1).
Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.
Galatsis
Paul
P
Pfizer Global R&D, Ann Arbor, MI 48105, USA. paul.galatsis@pfizer.com
Caprathe
Bradley
B
Gilmore
John
J
Thomas
Anthony
A
Linn
Kristin
K
Sheehan
Susan
S
Harter
William
W
Kostlan
Catherine
C
Lunney
Elizabeth
E
Stankovic
Charles
C
Rubin
John
J
Brady
Kenneth
K
Allen
Hamish
H
Talanian
Robert
R
D000577:Amides / Q000737:chemistry*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019802:Succinic Acid / Q000737:chemistry*
D000577:Amides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019802:Succinic Acid