Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors

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. In this report, we describe a rigorous
hit-to-lead optimization campaign supported by structural enablement,
which culminated in the discovery of brain-penetrant, candidate-quality
molecules as represented by compounds 22 and 24. 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 that serve to enable a potency- and selectivity-enhancing
increase in polarity and hydrogen bond donor (HBD) count while maintaining
a central nervous system-friendly profile typified by low levels of
transporter-mediated efflux and encouraging brain penetration in preclinical
models.