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Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson’s Disease Therapeutics

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Title
Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson’s Disease Therapeutics
Author(s)
Kewon Kim; Ahyoung Jang; Shin, Hochul; Ye, Inhae; Lee, Ji Eun; Kim, Taeho; Park, Hwangseo; Sungwoo Hong
Publication Date
2024-05
Journal
Journal of Medicinal Chemistry, v.67, no.7647, pp.7647 - 7662
Publisher
American Chemical Society
Abstract
The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson’s disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor’s brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics. © 2024 American Chemical Society.
URI
https://pr.ibs.re.kr/handle/8788114/15147
DOI
10.1021/acs.jmedchem.4c00520
ISSN
0022-2623
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > 1. Journal Papers (저널논문)
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