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 <b>1</b> by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound <b>12</b> which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite <b>14</b> 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 <b>15</b> and 4,6-diaminopyrimidine <b>16</b> as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs <b>17</b> and <b>18</b> 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 <b>23</b> with excellent LRRK2 potency and expanded selectivity <i>versus</i> off-target CLK2.