Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

被引：15

作者：

Bencsik, Peter ^{[1
,2
]}

Kupai, Krisztina ^{[3
]}

Goerbe, Aniko ^{[1
,2
]}

Kenyeres, Eva ^{[1
,2
]}

Varga, Zoltan V. ^{[4
]}

Paloczi, Janos ^{[4
]}

Gaspar, Renata ^{[3
]}

Kovacs, Laszlo ^{[5
]}

Weber, Lutz ^{[6
]}

Takacs, Ferenc ^{[5
]}

Hajdu, Istvan ^{[7
,8
]}

Fabo, Gabriella ^{[7
]}

Cseh, Sandor ^{[7
]}

Barna, Laszlo ^{[8
,9
]}

Csont, Tamas ^{[3
]}

Csonka, Csaba ^{[3
]}

Dorman, Gyoergy ^{[7
]}

Ferdinandy, Peter ^{[2
,4
]}

机构：

[1] Univ Szeged, Fac Med, Dept Biochem, Cardiovasc Res Grp, Szeged, Hungary

[2] Pharmahungary Grp, Szeged, Hungary

[3] Univ Szeged, Fac Med, Dept Biochem, Szeged, Hungary

[4] Semmelweis Univ, Fac Med, Dept Pharmacol & Pharmacotherapy, Budapest, Hungary

[5] Infarmat, Budapest, Hungary

[6] OntoChem GmbH, Halle, Saale, Germany

[7] Targetex Biosci, Dunakeszi, Hungary

[8] Hungarian Acad Sci, Inst Enzymol, Res Ctr Nat Sci, Budapest, Hungary

[9] Hungarian Acad Sci, Inst Expt Med, Microscopy Ctr, Budapest, Hungary

来源：

FRONTIERS IN PHARMACOLOGY | 2018年 / 9卷

关键词：

matrix metalloproteinase; MMP-2; inhibitor; heart; ischemia/reperfusion injury; cardioprotection; lead candidate; ISCHEMIA-REPERFUSION INJURY; HYDROXAMATE INHIBITORS; CATALYTIC DOMAIN; INFARCT SIZE; PEROXYNITRITE; DISCOVERY; DESIGN; TARGET;

D O I：

10.3389/fphar.2018.00296

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 mu M in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.

引用

页数：14

共 48 条

[1] Structural exploration for the refinement of anticancer matrix metalloproteinase-2 inhibitor designing approaches through robust validated multi-QSARs [J].