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

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.

• Authors: Min-Ho Nam, Jong-Hyun Park, Hyo Jung Song, Ji Won 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, Sangwook Kim, Soo-Jin Oh, Sang Ryong Jeon, Ki Duk Park, C Justin Lee
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 18 Issue 3 Pg. 1729-1747 (07 2021) ISSN: 1878-7479 [Electronic] United States
• PMID: 34611843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Monoamine Oxidase Inhibitors
• Monoamine Oxidase

Topics

• Animals
• Dose-Response Relationship, Drug
• Drug Development (methods)
• Female
• Macaca fascicularis
• Male
• Mice
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemistry, therapeutic use)
• Parkinsonian Disorders (chemically induced, drug therapy, enzymology, pathology)
• Rats
• Treatment Outcome