Discovery and Optimization of N‑Heteroaryl Indazole LRRK2 Inhibitors

Inhibition of leucine-rich repeat kinase 2 is a genetically
supported
mechanism for the treatment of Parkinson’s disease. We previously
disclosed the discovery of an indazole series lead that demonstrated
both safety and translational risks. The safety risks were hypothesized
to be of unknown origin, so structural diversity in subsequent chemical
matter was prioritized. The translational risks were identified due
to a low brain Kpu,u in nonhuman primate studies, which
raised concern over the use of an established peripheral biomarker
as a surrogate for central target engagement. Given these challenges,
the team sought to leverage structure- and property-based drug design
and expanded efflux transporter profiling to identify structurally
distinct leads with enhanced CNS drug-likeness. Herein, we describe
the discovery of a “reinvented” indazole series with
improved physicochemical properties and efflux transporter profiles
while maintaining excellent potency and off-target kinase selectivity,
which resulted in advanced lead, compound 23.