Journal of Medicinal Chemistry p. 7131 - 7143 (2018)
Update date:2022-07-29
Topics:
Morciano, Giampaolo
Preti, Delia
Pedriali, Gaia
Aquila, Giorgio
Missiroli, Sonia
Fantinati, Anna
Caroccia, Natascia
Pacifico, Salvatore
Bonora, Massimo
Talarico, Anna
Morganti, Claudia
Rizzo, Paola
Ferrari, Roberto
Wieckowski, Mariusz R.
Campo, Gianluca
Giorgi, Carlotta
Trapella, Claudio
Pinton, Paolo
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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