title: First-in-class pan caspase inhibitor developed for the treatment of liver disease.
abstract: A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
authors.affiliation: Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, CA 92121, USA. slinton@idun.com
authors.forename: Steven D
authors.initials: SD
authors.lastname: Linton
authors.forename: Teresa
authors.initials: T
authors.lastname: Aja
authors.forename: Robert A
authors.initials: RA
authors.lastname: Armstrong
authors.forename: Xu
authors.initials: X
authors.lastname: Bai
authors.forename: Long-Shiuh
authors.initials: LS
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Brett
authors.initials: B
authors.lastname: Ching
authors.forename: Patricia
authors.initials: P
authors.lastname: Contreras
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Diaz
authors.forename: Craig D
authors.initials: CD
authors.lastname: Fisher
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Fritz
authors.forename: Patricia
authors.initials: P
authors.lastname: Gladstone
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.forename: Julia
authors.initials: J
authors.lastname: Herrmann
authors.forename: Brad P
authors.initials: BP
authors.lastname: Hirakawa
authors.forename: Niel C
authors.initials: NC
authors.lastname: Hoglen
authors.forename: Kathy G
authors.initials: KG
authors.lastname: Jahangiri
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Kalish
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: Lalitha
authors.initials: L
authors.lastname: Kodandapani
authors.forename: Joseph
authors.initials: J
authors.lastname: Krebs
authors.forename: Jeff
authors.initials: J
authors.lastname: McQuiston
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.forename: Kip
authors.initials: K
authors.lastname: Nalley
authors.forename: Edward D
authors.initials: ED
authors.lastname: Robinson
authors.forename: Robert O
authors.initials: RO
authors.lastname: Sayers
authors.forename: Kristen
authors.initials: K
authors.lastname: Sebring
authors.forename: Alfred P
authors.initials: AP
authors.lastname: Spada
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ternansky
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tomaselli
authors.forename: Brett R
authors.initials: BR
authors.lastname: Ullman
authors.forename: Karen L
authors.initials: KL
authors.lastname: Valentino
authors.forename: Suzanne
authors.initials: S
authors.lastname: Weeks
authors.forename: David
authors.initials: D
authors.lastname: Winn
authors.forename: Joe C
authors.initials: JC
authors.lastname: Wu
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Cheng-zhi
authors.initials: CZ
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001682:Biological Availability; D053148:Caspase 3; D061945:Caspase Inhibitors; D002779:Cholestasis / Q000188:drug therapy / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D006207:Half-Life; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D051379:Mice; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3