KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson's Disease

  • Neurotherapeutics. 2021 Jul;18(3):1729-1747. doi: 10.1007/s13311-021-01097-4.
Min-Ho Nam  #  1  2 ,  Jong-Hyun Park  #  3  4 ,  Hyo Jung Song  #  3 ,  Ji Won Choi  3 ,  Siwon Kim  3  4 ,  Bo Ko Jang  3 ,  Hyung Ho Yoon  5 ,  Jun Young Heo  1  6 ,  Hyowon Lee  1 ,  Heeyoung An  7 ,  Hyeon Jeong Kim  3  8 ,  Sun Jun Park  3  4 ,  Doo-Wan Cho  9 ,  Young-Su Yang  9 ,  Su-Cheol Han  9 ,  Sangwook Kim  10 ,  Soo-Jin Oh  1  3 ,  Sang Ryong Jeon  5 ,  Ki Duk Park  11  12 ,  C Justin Lee  13
Affiliations
  • 1. Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
  • 2. Department of KHU-KIST Convergence Science and Technology, Kyung Hee University, Seoul, 02453, Korea.
  • 3. Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea.
  • 4. Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
  • 5. Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
  • 6. Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • 7. Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea.
  • 8. Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
  • 9. Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea.
  • 10. Neurobiogen Co., LTD, Seocho-gu, Seoul, 9, Republic of Korea.
  • 11. Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea. [email protected].
  • 12. Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea. [email protected].
  • 13. Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 34611843 DOI: 10.1007/s13311-021-01097-4
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.

Keywords
MAO-B inhibitor; Parkinson’s disease; Pharmacology; Reactive glia; α-Aminoamide derivative.
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