The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson’s disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. Here, we describe a rigorous hit-to-lead optimization campaign supported by structural-enablement which culminated in the discovery of brain-penetrant, candidate-quality molecules. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements which serve to enable an increase in topological polar surface area (tPSA) and hydrogen bond donor (HBD) count while maintaining a CNS-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Structure-guided discovery of aminoquinazolines as CNS-penetrant and selective LRRK2 inhibitors

ACS Spring 2022

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