First-in-class pan caspase inhibitor developed for the treatment of liver disease.
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.
Linton
Steven D
SD
Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, CA 92121, USA. slinton@idun.com
Aja
Teresa
T
Armstrong
Robert A
RA
Bai
Xu
X
Chen
Long-Shiuh
LS
Chen
Ning
N
Ching
Brett
B
Contreras
Patricia
P
Diaz
Jose-Luis
JL
Fisher
Craig D
CD
Fritz
Lawrence C
LC
Gladstone
Patricia
P
Groessl
Todd
T
Gu
Xin
X
Herrmann
Julia
J
Hirakawa
Brad P
BP
Hoglen
Niel C
NC
Jahangiri
Kathy G
KG
Kalish
Vincent J
VJ
Karanewsky
Donald S
DS
Kodandapani
Lalitha
L
Krebs
Joseph
J
McQuiston
Jeff
J
Meduna
Steven P
SP
Nalley
Kip
K
Robinson
Edward D
ED
Sayers
Robert O
RO
Sebring
Kristen
K
Spada
Alfred P
AP
Ternansky
Robert J
RJ
Tomaselli
Kevin J
KJ
Ullman
Brett R
BR
Valentino
Karen L
KL
Weeks
Suzanne
S
Winn
David
D
Wu
Joe C
JC
Yeo
Pauline
P
Zhang
Cheng-zhi
CZ
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
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