tro-40303 and alisporivir

The mitochondrial permeability transition pore (PTP) is now recognized as playing a key role in a wide variety of human diseases whose common pathology may be based in mitochondrial dysfunction. Recently, PTP assays have been adapted to high-throughput screening approaches to identify small molecules specifically inhibiting the PTP. Following extensive secondary chemistry, the most potent inhibitors of the PTP described to date have been developed. This review will provide an overview of each of these screening efforts, use of resulting compounds in animal models of PTP-based diseases, and problems that will require further study. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Topics: Anilides; Benzamidines; Cyclosporine; Drug Design; High-Throughput Screening Assays; Isoxazoles; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Permeability Transition Pore; Oximes; Peptides, Cyclic; Quinolinium Compounds; Secosteroids; Structure-Activity Relationship

Mitochondria are critical for sustaining life, not only as the essential powerhouses of cells but as critical mediators of cell survival and death. Mitochondrial dysfunction has been identified as a key perturbation underlying numerous pathologies including myocardial ischemia-reperfusion injury and the subsequent development of impaired left ventricular systolic function and compensatory cardiac hypertrophy. This article outlines the role of mitochondrial dysfunction in these important cardiac pathologies and highlights current cardioprotective strategies and their clinical efficacy in acute myocardial infarction and heart failure patients. Finally, we explore novel mitochondrial targets and evaluate their potential future translation for clinical cardioprotection.

Topics: Cardiopulmonary Bypass; Cardiotonic Agents; Cardiovascular Diseases; Cell Death; Cyclosporine; Free Radical Scavengers; Humans; Immunosuppressive Agents; Ischemic Postconditioning; Ischemic Preconditioning; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitophagy; Myocytes, Cardiac; Organophosphorus Compounds; Oximes; Percutaneous Coronary Intervention; Reactive Oxygen Species; Secosteroids; Ubiquinone