Concurrent Optimizations of Efficacy and Blood–Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson’s Disease Therapeutics
Kewon Kim, Ahyoung Jang, Ho‐Chul Shin, Inhae Ye, Ji‐Eun Lee, Taeho Kim, Hwangseo Park, Sungwoo Hong
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.