Send to

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

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.

Author information

Maria Pia Hospital , GVM Care & Research , 10132 , Torino , Italy.
Maria Cecilia Hospital , GVM Care & Research , 48033 , Cotignola , Ravenna , Italy.
Cardiovascular Institute , Azienda Ospedaliera-Universitaria S. Anna , Cona, Ferrara 44121 , Italy.
Department of Biochemistry, Nencki Institute of Experimental Biology , Polish Academy of Sciences , Warsaw 02-093 , Poland.


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.

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center