発見および最適化されたピロロピリミジン類：非常に強力で選択的、かつ脳透過性の高いLRRK2阻害剤

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for Parkinson's disease. We report herein the discovery of pyrrolopyrimidine analogs as potent and selective LRRK2 kinase inhibitors. Elucidation of the structure-activity relationship (SAR) of the kinase-inhibitor-focused screening lead compound 1 led to the development of compound 39 (GSK3357679) that shows excellent cellular potency, oral bioavailability, brain-penetration, and excellent PK/PD correlation in animal studies. The SAR optimization of the biological and pharmacokinetic profiles of the compounds are described. The pharmacodynamic characteristics for extended oral dosing studies in rodents are also presented.