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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. This led to the discovery of 3,5-diaminopyridine
15
and 4,6-diaminopyrimidine
16
as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs
17
and
18
led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole
23
with excellent LRRK2 potency and expanded selectivity
versus
off-target CLK2.
The evolution of picolinamide derived LRRK2 inhibitors with improved kinase off target selectivity and de-risked for AMES mutagenicity.