Discovery of a Chiral 2,4-Substituted Pyrrolo[2,3‑d]pyrimidine as a Potent, Selective, and Orally Bioavailable LRRK2 Inhibitor

Inhibition of leucine-rich repeat kinase (LRRK2) activity with small molecules has emerged as a potential novel therapeutic target for Parkinson’s disease (PD). We have previously reported the identification of SRI-29132 as a potent LRRK2 inhibitor, but the presence of a 6-thioether moiety, which is an oxidative liability, precludes its further development. Herein, we report another hit-to-lead optimization study that led to the discovery of the chiral 2,4-substituted pyrrolo[2,3-d]pyrimidine series as potent LRRK2 inhibitors. Our lead analog 6, derived from a high-throughput screening hit SRI-31255, exhibits excellent LRRK2 inhibition activity and, high selectivity across the kinome. Further, the molecule has acceptable absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetic (PK) properties, as well as brain permeability and no off-target liabilities. This new class of compounds serves as a novel series for further study in the development of LRRK2 inhibitors for therapy.