Discovery of novel thienopyrimidine derivatives as LRRK2 inhibitors

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is considered a promising therapeutic target for Parkinson's disease, Crohn's disease, and cancer. Despite considerable research, none of these inhibitors are available for clinical application. Herein, we designed and synthesized novel thienopyrimidine derivatives by a bioisosteric replacement and investigated their structure-activity relationships. Thieno[3,2-d]pyrimidine derivative 22 showed the most potent inhibitory activity and inhibited both wild-type and G2019S mutant LRRK2 with IC50 values of 30 and 14 nM, respectively.