Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F 1/F O-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction

J Med Chem. 2018 Aug 23;61(16):7131-7143. doi: 10.1021/acs.jmedchem.8b00278. Epub 2018 Aug 9.

Abstract

Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemistry
  • Animals
  • Cardiotonic Agents / chemistry
  • Cardiotonic Agents / pharmacology*
  • Disease Models, Animal
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membrane Transport Proteins / drug effects
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors*
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Molecular Targeted Therapy
  • Myocardial Infarction / complications
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / drug therapy*
  • Protein Subunits / antagonists & inhibitors
  • Rats, Wistar
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Protein Subunits
  • Small Molecule Libraries
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases
  • decane