Design and Synthesis of Pyrrolo[2,3-]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.

Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2)-2-Methylpyrrolidin-1-yl derivative (LRRK2 G2019S c 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of gave the 2-[(1,3-dimethyl-1-pyrazol-4-yl)amino] derivative . Optimization of afforded diastereomeric oxolan-3-yl derivatives and , which demonstrated a favorable PK profile, although they displayed species disconnects in the PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds and demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.