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J Cardiovasc Pharmacol. 2014 Apr;63(4):316-322. doi: 10.1097/FJC.0000000000000053.

A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse.

Author information

1
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
2
Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
3
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
4
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
5
Department of Pharmacotherapy and Outcome Studies, Virginia Commonwealth University, Richmond, VA, USA.
#
Contributed equally

Abstract

BACKGROUND:

The formation of the NLRP3 inflammasome in the heart during acute myocardial infarction amplifies the inflammatory response and mediates further damage. Glyburide has NLRP3 inhibitory activity in vitro but requires very high doses in vivo, associated with hypoglycemia. The aim of this study was to measure the effects on the NLRP3 inflammasome of 16673-34-0, an intermediate substrate free of the cyclohexylurea moiety, involved in insulin release.

METHODS AND RESULTS:

We synthesized 16673-34-0 (5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide) that displayed no effect on glucose metabolism. HL-1 cardiomyocytes were treated with lipopolysaccharide and ATP to induce the formation of the NLRP3 inflammasome, measured as increased caspase-1 activity and cell death, and 16673-34-0 prevented such effects. 16673-34-0 was well tolerated with no effects on the glucose levels in vivo. Treatment with 16673-34-0 in a model of acute myocardial infarction because of ischemia and reperfusion significantly inhibited the activity of inflammasome (caspase-1) in the heart by 90% (P < 0.01) and reduced infarct size, measured at pathology (by >40%, P < 0.01) and with troponin I levels (by >70%, P < 0.01).

CONCLUSIONS:

The small molecule 16673-34-0, an intermediate substrate in the glyburide synthesis free of the cyclohexylurea moiety, inhibits the formation of the NLRP3 inflammasome in cardiomyocytes and limits the infarct size after myocardial ischemia-reperfusion in the mouse, without affecting glucose metabolism.

PMID:
24336017
PMCID:
PMC3980088
DOI:
10.1097/FJC.0000000000000053
[Indexed for MEDLINE]
Free PMC Article

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