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Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Jun 26; Vol. 57 (12), pp. 5333-47. Date of Electronic Publication: 2014 Jun 11. - Publication Year :
- 2014
-
Abstract
- In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
- Subjects :
- 1-Naphthylamine chemical synthesis
1-Naphthylamine chemistry
1-Naphthylamine pharmacology
Acrylamides chemical synthesis
Acrylamides pharmacology
Anilides chemical synthesis
Anilides pharmacology
Animals
Calcium metabolism
Cinnamates chemical synthesis
Cinnamates pharmacology
Female
Male
Mice, Inbred C57BL
Mitochondria, Heart metabolism
Mitochondria, Liver metabolism
Mitochondrial Membrane Transport Proteins metabolism
Mitochondrial Permeability Transition Pore
Mitochondrial Swelling drug effects
Myocardial Infarction drug therapy
Myocardial Infarction metabolism
Myocardial Reperfusion Injury metabolism
Rabbits
Stereoisomerism
Structure-Activity Relationship
1-Naphthylamine analogs & derivatives
Acrylamides chemistry
Anilides chemistry
Cinnamates chemistry
Mitochondrial Membrane Transport Proteins antagonists & inhibitors
Myocardial Reperfusion Injury drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24918261
- Full Text :
- https://doi.org/10.1021/jm500547c