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

• DOI: 10.1007/s13311-021-01097-4
• Publication Date: 2021-10-06T03:01:31Z
• 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
• Keywords: Male; 0303 health sciences; Monoamine Oxidase Inhibitors; Dose-Response Relationship, Drug; Rats; 3. Good health; Macaca fascicularis; Mice; 03 medical and health sciences; Treatment Outcome; Drug Development; Parkinsonian Disorders; Animals; Original Article; Female; Monoamine Oxidase

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.