Discovery of azaspirocyclic 1H-3,4,5-Trisubstitued pyrazoles as novel G2019S-LRRK2 selective kinase inhibitors.

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1 H -pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1 H -pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1 H -pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1 H -3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds. [Display omitted] • HIGHLIGHTS: Discovery of Azaspirocyclic 1 H- 3,4,5 - Trisubstitued Pyrazoles as Novel G2019S-LRRK2 Selective Kinase Inhibitors. • Mutations in the LRRK2 gene are the most common genetic causes of Parkinson's Disease. • G2019S is the most common inherited LRRK2 mutation and increases kinase activity. • We identified highly kinome and G2019S-selective inhibitors with in vivo efficacy. • Azaspirocyclic bioisostere of phenylsulfonamide enables improved PK properties. [ABSTRACT FROM AUTHOR]