Parkinson’s Disease (PD), a progressive, neurodegenerative disorder characterized by loss of dopaminergic neurons in the brain, is associated with motor and non-motor pathologies including tremors, bradykinesia, muscular rigidity, and postural and gait impairment. Robust clinical genetic studies have identified mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene as a causative factor in familial PD. This renders LRRK2 a compelling CNS target as is evident by the crowded competitor landscape. Our discovery team embarked on developing novel macrocycles as potential best-in-class LRRK2 inhibitors, with particular emphasis on ligand efficiency, kinase selectivity, pharmacokinetics, and blood-brain-barrier penetration. This talk will detail how these efforts identified LRRK2 inhibitors with favorable profiles. Key challenges addressed during this journey will also be highlighted, including: (1) <i>in vivo</i> metabolite formation, (2) solution-degradant formation, and (3) synthetic route remediation.

Divergent optimization of macrocyclic LRRK2 inhibitors: Pursuit of best-in-class treatments for Parkinson’s disease

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.