Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo

Abstract

In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.

Calcium and reactive oxygen species in regulation of the mitochondrial permeability transition and of programmed cell death in yeast

“…We have already found that genetic ablation of the e and/or g subunits, whose presence is important for F-ATP synthase dimerization [101], confers at least partial resistance to PTP opening [65]. Identification of the cysteine residues responsible for the sensitizing effects of oxidative stress and the availability of novel, CyP-independent PTP inhibitors [102-104] should soon allow a stringent test of this hypothesis.…”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…The mPTP inhibitors, such as cyclosporin-A (CsA) (153, 154), cyclophilin-D (155), cinnamic anilides (156), and antioxidants are known to prevent the mPTP opening. Yin et al reported a NP system containing CsA which when used in combination with adipose-derived stem cell (ASCs) in a swine model of myocardial infarction showed therapeutic benefits (157).…”

Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria

“…Despite identification of small molecule inhibitors of mPT presenting an obvious therapeutic opportunity, the availability and development of such agents remains limited. A number of groups have identified novel molecules modulating mitochondrial propensity for permeability transition30323334353637. However, as yet, reports of positive clinical development are yet to emerge.…”