Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F1/FO-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.
Giampaolo Morciano  1  2 ,  Delia Preti ,  Gaia Pedriali  2 ,  Giorgio Aquila ,  Sonia Missiroli ,  Anna Fantinati ,  Natascia Caroccia ,  Salvatore Pacifico ,  Massimo Bonora ,  Anna Talarico ,  Claudia Morganti ,  Paola Rizzo  2 ,  Roberto Ferrari  2  3 ,  Mariusz R Wieckowski  4 ,  Gianluca Campo  2  3 ,  Carlotta Giorgi ,  Claudio Trapella ,  Paolo Pinton  2
Affiliations
  • 1. Maria Pia Hospital , GVM Care & Research , 10132 , Torino , Italy.
  • 2. Maria Cecilia Hospital , GVM Care & Research , 48033 , Cotignola , Ravenna , Italy.
  • 3. Cardiovascular Institute , Azienda Ospedaliera-Universitaria S. Anna , Cona, Ferrara 44121 , Italy.
  • 4. Department of Biochemistry, Nencki Institute of Experimental Biology , Polish Academy of Sciences , Warsaw 02-093 , Poland.
PMID: 30060655 DOI: 10.1021/acs.jmedchem.8b00278
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.

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