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OHSU # 2750 — Compositions for treatment of neurological and oxidative stress disorders

Summary

Dysfunction of the mitochondrial permeability transition pore (mtPTP) is associated with accumulation of reactive oxygen species (ROS) in many disease states. Researchers at Oregon Health & Science University, University of Kansas, and University of Padova have developed highly potent and stable small molecule inhibitors of mtPTP.

Technology Overview

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 hearts.

Publications

Antonucci et al., A novel class of cardioprotective small-molecule PTP inhibitors. Pharm Research 151 (2020): 104548. Link

Sileikyte et al., Second-Generation Inhibitors of Mitochondrial Permeability Transition Pore with improved Plasma Stability. Chem MedChem 14 (2019): 1997-1782. Link

Forte, M. et al. Discovery, Synthesis, and Optimization of Diarylisoxazole-3- carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore, Chem MedChem 10 (2015): 10:1655-71. Link

Licensing Opportunity

This technology is available for licensing and co-development.

Inventors:

Patents

Filed United States
Published European Patent Convention 4003009

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