Asset

  • No.

    130

  • Asset Title

    Compositions for Treatment of Neurological and Oxidative Stress Disorders

  • Organization

    Oregon Health and Science University

  • Product Type

    Small molecule

  • Therapeutic Area

    Cardiovascular disease

  • Development Stage

    Hit To Lead or Lead Optimization

  • Technical Summary

    • 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. 

  • Patent

    US20220289690A1

  • Publication

    • 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)

  • Attachment

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