Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic strategy for Parkinson's disease, supported by genetic evidence.
• Previous indazole lead compounds exhibited safety concerns and poor brain penetration (low Kp_u,u), hindering central target engagement assessment.

Purpose of the Study:

• To discover structurally distinct, CNS-penetrant indazole-based compounds with improved drug-like properties.
• To address safety and translational risks associated with earlier lead compounds for Parkinson's disease therapy.

Main Methods:

• Employed structure- and property-based drug design principles.
• Conducted expanded efflux transporter profiling to assess blood-brain barrier permeability.
• Prioritized structural diversity to mitigate safety risks of unknown origin.

Main Results:

• Successfully developed a "reinvented" indazole series with significantly enhanced physicochemical properties.
• Achieved improved efflux transporter profiles, indicating better CNS drug-likeness.
• Maintained high potency against the LRRK2 target and excellent off-target kinase selectivity.

Conclusions:

• The reinvented indazole series represents a promising advancement in LRRK2 inhibitor development for Parkinson's disease.
• Compound 23, an advanced lead, demonstrates a favorable profile for CNS-directed therapy, overcoming prior limitations.