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Compositions for Treatment of Neurological and Oxidative Stress Disorders
Oregon Health and Science University
Small molecule
Cardiovascular disease
Hit To Lead or Lead Optimization
• The mitochondrial permeability transition pore (mtPTP) plays a key role in a wide variety of human diseases whose common pathology may be based in mitochondrial dysfunction; however, there are few small molecule inhibitors of mtPTP. The leading mtPTP inhibitor CsA also has limitations, including a likely indirectly mechanism of inhibition, an inability to cross the blood brain barrier, and immunosuppressive side effects.
• The laboratories of Drs. Forte, Bernardi and Cohen have developed and optimized small molecule mtPTP inhibitors. The lead compounds demonstrate the following:
➢ Picomolar IC50s for inhibiting the opening of mtPTP
➢ Inhibition of mtPTP opening, independent of cyclophilin D, and synergism when combined with CsA.
➢ Inhibition of mitochondrial swelling in murine liver cells.
➢ Absence of mitochondrial toxicity as demonstrated by measurements of mitochondrial membrane potential, oxygen consumption rates and ATP synthesis.
➢ High stability in human serum over the course of several hours.
➢ Reduction in muscular dystrophy symptoms in zebrafish models.
➢ Cardioprotective effects in adult mouse ventricular myocytes, human iPSc-derived cardiomyocytes, and in ex vivo in perfused heart.
US20220289690A1
• A novel class of cardioprotective small-molecule PTP inhibitors. Pharm Research, (2020)
• Second-Generation Inhibitors of Mitochondrial Permeability Transition Pore with improved Plasma Stability. Chem MedChem. (2019)
• Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore, Chem MedChem. (2015)
