Solomon D Kattar, Anmol Gulati, Kaila A Margrey, Mitchell H Keylor, Michael Ardolino, Xin Yan, Rebecca Johnson, Rachel L Palte, Spencer E McMinn, Lisa Nogle, Jing Su, Dong Xiao, Jennifer Piesvaux, Susi Lee, Laxminarayan G Hegde, Janice D Woodhouse, Robert Faltus, Lily Y Moy, Tina Xiong, Paul J Ciaccio, Kara Pearson, Mayankbhai Patel, Karin M Otte, Cheryl E G Leyns, Matthew E Kennedy, David Jonathan Bennett, Erin F DiMauro, Matthew J Fell, Peter H Fuller
Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties...
October 20, 2023: Journal of Medicinal Chemistry