According to the International Diabetes Federation (IDF), diabetes affects close to 400 million people worldwide and caused 500 billion Euros in health expenditure in 2013. In preclinical and clinical trials, the NMDA receptor antagonist dextrorphan (DXO) and its prodrug dextromethorphan have been shown to harbor antidiabetic properties (Marquard et al., Nat Med 2015). In addition, DXO was shown to protect mouse and human pancreatic beta cells from cell death during a diabetogenic setting. DXO is well tolerated and sold as over-the-counter (OTC) medication for more than 50 years. However, adverse events are observed, which are likely caused by the action of DXO on the central nervous system (CNS). Here, the scientists developed DXO-derivatives that do not efficiently pass the blood brain barrier (BBB), and thus should cause fewer adverse effects on the CNS, but maintain their antidiabetic properties. Therefore, the derivatives might maintain the good safety profile and antidiabetic properties of its starting substance dextrorphan, but with fewer adverse effects. The inventors now aim to demonstrate the expected novel clinical benefit in clinical studies.
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