Article
Author: Minnihan, Ellen C. ; Kattar, Solomon ; Liu, Ping ; Martinot, Theodore A. ; Graham, Thomas H. ; Morriello, Gregori J. ; Fell, Matthew J. ; Bennett, David Jonathan ; Tong, Ling ; Pio, Barbara ; Keylor, Mitchell H. ; Moy, Lily Y. ; Liu, Weiguo ; McMinn, Spencer E. ; Neelamkavil, Santhosh ; Palte, Rachel L. ; DeMong, Duane E. ; Piesvaux, Jennifer A. ; Nogle, Lisa ; Gulati, Anmol ; Gunaydin, Hakan ; Xiong, Tina ; Chau, Ryan W. ; DiMauro, Erin F. ; Simov, Vladimir ; Ciaccio, Paul ; Acton, John J. ; Ardolino, Michael J. ; Hegde, Laxminarayan G. ; Yan, Xin ; Ellis, J. Michael ; Otte, Karin M. ; Lesburg, Charles A. ; Methot, Joey L. ; Candito, David A. ; Lapointe, Blair T. ; Kurukulasuriya, Ravi ; Kennedy, Matthew E. ; Su, Jing ; Scott, Jack D. ; Woodhouse, Janice D. ; Yu, Hongshi ; Faltus, Robert ; Fuller, Peter H. ; Maddess, Matthew L. ; Wood, Harold B.
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-sp2 cross-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.