Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

ABSTRACT: The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames

SUBMITTER: Gulati A 

PROVIDER: S-EPMC8292993 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature