1. KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson’s Disease
- Author
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Hyowon Lee, C. Justin Lee, Siwon Kim, Sang-Wook Kim, Sang Ryong Jeon, Soo Jin Oh, Min-Ho Nam, Jun Young Heo, Jiwon Choi, Sun Jun Park, Hyung Ho Yoon, Hyo Jung Song, Jong Hyun Park, Ki Duk Park, Heeyoung An, Bo Ko Jang, Doo-Wan Cho, Su-Cheol Han, Young-Su Yang, and Hyeon Jeong Kim
- Subjects
Male ,Monoamine Oxidase Inhibitors ,Parkinson's disease ,α-Aminoamide derivative ,Monoamine oxidase ,Nigrostriatal pathway ,Pharmacology ,Neuroprotection ,Mice ,chemistry.chemical_compound ,Drug Development ,Parkinsonian Disorders ,medicine ,Animals ,Pharmacology (medical) ,MAO-B inhibitor ,Monoamine Oxidase ,Reactive glia ,Dose-Response Relationship, Drug ,business.industry ,MPTP ,Parkinsonism ,medicine.disease ,Rats ,Macaca fascicularis ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Toxicity ,Parkinson’s disease ,Original Article ,Female ,Neurology (clinical) ,Monoamine oxidase B ,business - 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. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01097-4.
- Published
- 2021