학술논문
Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1H-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease
Document Type
Article
Author
Candito, David A.; Simov, Vladimir; Gulati, Anmol; Kattar, Solomon; Chau, Ryan W.; Lapointe, Blair T.; Methot, Joey L.; DeMong, Duane E.; Graham, Thomas H.; Kurukulasuriya, Ravi; Keylor, Mitchell H.; Tong, Ling; Morriello, Gregori J.; Acton, John J.; Pio, Barbara; Liu, Weiguo; Scott, Jack D.; Ardolino, Michael J.; Martinot, Theodore A.; Maddess, Matthew L.; Yan, Xin; Gunaydin, Hakan; Palte, Rachel L.; McMinn, Spencer E.; Nogle, Lisa; Yu, Hongshi; Minnihan, Ellen C.; Lesburg, Charles A.; Liu, Ping; Su, Jing; Hegde, Laxminarayan G.; Moy, Lily Y.; Woodhouse, Janice D.; Faltus, Robert; Xiong, Tina; Ciaccio, Paul; Piesvaux, Jennifer A.; Otte, Karin M.; Kennedy, Matthew E.; Bennett, David Jonathan; DiMauro, Erin F.; Fell, Matthew J.; Neelamkavil, Santhosh; Wood, Harold B.; Fuller, Peter H.; Ellis, J. Michael
Source
Journal of Medicinal Chemistry; 20220101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson’s disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3–sp2cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.