Design and development of novel, potent and brain penetrant cyclic LRRK2 inhibitors for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a debilitating and progressive neurodegenerative disorder, where disease-modifying therapy (DMT) represents a major unmet clinical need. Advances in the understanding of underlying pathogenesis reveal the potential therapeutic value of inhibitors targeting leucine-rich repeat kinase 2 (LRRK2) for PD treatment. Guided by structure-based docking and ligand-based rational design, herein we reported the discovery of novel pyrrolopyrimidine-derived cyclic LRRK2 inhibitors. Multiple compounds exhibited potent in vitro inhibitory activity against both wild-type and G2019S mutant LRRK2, among which compound II-5 was identified through stepwise structural optimization aimed at balancing potency and drug-like properties. Compound II-5 demonstrated favorable pharmacokinetic (PK) characteristics, suitable blood-brain barrier (BBB) permeability, as well as sustained and effective reduction of pS935 level, highlighting it as a potent preclinical candidate compound for further development in the field of Parkinson's disease therapeutics.