CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF
Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.
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Paragraph 0073; 0075
(2019/04/05)
Structure-activity relationship study of a series of caspase inhibitors containing γ-amino acid moiety for treatment of cholestatic liver disease
A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.
METHODS OF USING CASPASE INHIBITORS IN TREATMENT OF LIVER DISEASE
Provided herein are methods and compositions for treatment of an elevated MELD score or Child-Pugh score or their components by administering a of a caspase inhibitor alone or in combination with current treatments for liver disease.
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Paragraph 00157
(2017/07/14)
TREATMENT OF THE COMPLICATIONS OF CHRONIC LIVER DISEASE
Provided herein are methods and compositions for treatment of a portal hypertension and cirrhosis by administering a of a caspase inhibitor alone or in combination with current treatments for portal hypertension. Also provided are methods and compositions
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Paragraph 0158
(2016/08/17)
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 α-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.,Aja, Teresa,Armstrong, Robert A.,Bai, Xu,Chen, Long-Shiuh,Chen, Ning,Ching, Brett,Contreras, Patricia,Diaz, Jose-Luis,Fisher, Craig D.,Fritz, Lawrence C.,Gladstone, Patricia,Groessl, Todd,Gu, Xin,Herrmann, Julia,Hirakawa, Brad P.,Hoglen, Niel C.,Jahangiri, Kathy G.,Kalish, Vincent J.,Karanewsky, Donald S.,Kodandapani, Lalitha,Krebs, Joseph,McQuiston, Jeff,Meduna, Steven P.,Nalley, Kip,Robinson, Edward D.,Sayers, Robert O.,Sebring, Kristen,Spada, Alfred P.,Ternansky, Robert J.,Tomaselli, Kevin J.,Ullman, Brett R.,Valentino, Karen L.,Weeks, Suzanne,Winn, David,Wu, Joe C.,Yeo, Pauline,Zhang, Cheng-Zhi
p. 6779 - 6782
(2007/10/03)
Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
Linton, Steven D.,Aja, Teresa,Allegrini, Peter R.,Deckwerth, Thomas L.,Diaz, Jose-Luis,Hengerer, Bastian,Herrmann, Julia,Jahangiri, Kathy G.,Kallen, Joerg,Karanewsky, Donald S.,Meduna, Steven P.,Nalley, Kip,Robinson, Edward D.,Roggo, Silvio,Rovelli, Giorgio,Sauter, Andre,Sayers, Robert O.,Schmitz, Albert,Smidt, Robert,Ternansky, Robert J.,Tomaselli, Kevin J.,Ullman, Brett R.,Wiessner, Christoph,Wu, Joe C.
p. 2685 - 2691
(2007/10/03)
C-terminal modified oxamyl dipeptides as inhibitors of the ICE-ced-3 family of cysteine proteases
This invention is directed to novel oxamyl dipeptide ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as to the use of such compositions in the treatment of patients su
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(2008/06/13)
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