Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson’s Disease
Elsie C. Yu·Peter H. Fuller·Xin Yan·Kaitlyn M. Logan·D. Li·Anmol Gulati·Kelsey E. Poremba·Michael J. Ardolino·Jing Su·Dong Xiao·R.L. Palte·Spencer E. McMinn·Lisa Nogle·Donovon A. Adpressa·Samantha A. Burgess·Tina Xiong·Karin M. Otte·Harry R. Chobanian·Alan Bass·S. Lee·Kara Pearson·Eric Messina·Michael Parisi·John E. Barnum·Zhanna Sobol·Paul J. Ciaccio·Erin F. DiMauro·Matthew J. Fell·Hua Zhou
Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder for which treatments are limited. Herein, we describe the invention of a macrocyclic LRRK2 inhibitor lead chemical series. Rigorous application of knowledge-, structure-, and property-based drug design culminated in the discovery of compound <b>7</b>, which was profiled extensively before it was determined to be clastogenic, wh