title: Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1).
abstract: 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.
authors.affiliation: Pfizer Global R&D, Ann Arbor, MI 48105, USA. paul.galatsis@pfizer.com
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
authors.forename: Bradley
authors.initials: B
authors.lastname: Caprathe
authors.forename: John
authors.initials: J
authors.lastname: Gilmore
authors.forename: Anthony
authors.initials: A
authors.lastname: Thomas
authors.forename: Kristin
authors.initials: K
authors.lastname: Linn
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.forename: William
authors.initials: W
authors.lastname: Harter
authors.forename: Catherine
authors.initials: C
authors.lastname: Kostlan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lunney
authors.forename: Charles
authors.initials: C
authors.lastname: Stankovic
authors.forename: John
authors.initials: J
authors.lastname: Rubin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Brady
authors.forename: Hamish
authors.initials: H
authors.lastname: Allen
authors.forename: Robert
authors.initials: R
authors.lastname: Talanian
mesh_terms: 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*
chemical_list: D000577:Amides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019802:Succinic Acid