Abstract

Background and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinsons disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD. Experimental ApproachWe designed and synthesized -aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates. Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the -aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates. Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD. Representative Schematic O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY What is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor. MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis. What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD. KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates. What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinsons disease. Reversible MAO-B inhibitors could be more effective for treatment of Parkinsons disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.