KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson's Disease
Min‐Ho Nam, Jong‐Hyun Park, Hyo Jung Song, Jin‐Sung Choi, Siwon Kim, Bo Ko Jang, Hyung Ho Yoon, Jun Young Heo, Hyowon Lee, Heeyoung An, Hyeon Jeong Kim, Sun Jun Park, Doo‐Wan Cho, Young‐Su Yang, Su-Cheol Han, Sang‐Wook Kim, Soo‐Jin Oh, Sang Ryong Jeon, Ki Duk Park, C. Justin Lee
Abstract
Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson's disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.