title: A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse.
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.
  
  
  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.
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.|Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Carlo
authors: C
authors: Marchetti
authors: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors: Jeremy
authors: J
authors: Chojnacki
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
authors: Stefano
authors: S
authors: Toldo
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.|Department of Pharmacotherapy and Outcome Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors: Eleonora
authors: E
authors: Mezzaroma
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
authors: Nicla
authors: N
authors: Tranchida
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
authors: Scott W
authors: SW
authors: Rose
authors: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Massimo
authors: M
authors: Federici
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.|Department of Pharmacotherapy and Outcome Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors: Shijun
authors: S
authors: Zhang
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.|Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
authors: Antonio
authors: A
authors: Abbate
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000593118:5-chloro-2-methoxy-N-(2-(4-sulfamoylphenyl)ethyl)benzamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001786:Blood Glucose; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013449:Sulfonamides