Back to Search
Start Over
Discovery of novel TNNI3K inhibitor suppresses pyroptosis and apoptosis in murine myocardial infarction injury.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Jul 01; Vol. 197, pp. 112314. Date of Electronic Publication: 2020 Apr 15. - Publication Year :
- 2020
-
Abstract
- Myocardial infarction (MI) injury is a highly lethal syndrome that has, until recently, suffered from a lack of clinically efficient targeted therapeutics. The cardiac troponin I interacting kinase (TNNI3K) exacerbates ischemia-reperfusion (IR) injury via oxidative stress, thereby promoting cardiomyocyte death. In this current study, we designed and synthesized 35 novel TNNI3K inhibitors with a pyrido[4,5]thieno[2,3-d] pyrimidine scaffold. In vitro results indicated that some of the inhibitors exhibited sub-micromolar TNNI3K inhibitory capacity and good kinase selectivity, as well as cytoprotective activity, in an oxygen-glucose deprivation (OGD) injury cardiomyocyte model. Furthermore, investigation of the mechanism of the representative derivative compound 6o suggested it suppresses pyroptosis and apoptosis in cardiomyocytes by interfering with p38MAPK activation, which was further confirmed in a murine myocardial infarction injury model. In vivo results indicate that compound 6o can markedly reduce myocardial infarction size and alleviate cardiac tissue damage in rats. In brief, our results provide the basis for further development of novel TNNI3K inhibitors for targeted MI therapy.<br />Competing Interests: Declaration of competing interest The authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Binding Sites
Cardiotonic Agents chemical synthesis
Cardiotonic Agents metabolism
Cell Line
Drug Design
MAP Kinase Signaling System drug effects
Male
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Structure
Myocardial Infarction prevention & control
Protein Binding
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors metabolism
Protein Serine-Threonine Kinases metabolism
Rats
Reactive Oxygen Species metabolism
Structure-Activity Relationship
Apoptosis drug effects
Cardiotonic Agents therapeutic use
Myocardial Infarction drug therapy
Protein Kinase Inhibitors therapeutic use
Protein Serine-Threonine Kinases antagonists & inhibitors
Pyroptosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 197
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32344181
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112314