Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors
Mitchell H. Keylor, Anmol Gulati, Solomon D. Kattar, Rebecca Johnson, Ryan Chau, Kaila A. Margrey, Michael J. Ardolino, Cayetana Zárate, Kelsey E. Poremba, Vladimir Simov, Gregori J. Morriello, John J. Acton, Barbara Pio, Xin Yan, R.L. Palte, Spencer E. McMinn, Lisa Nogle, Charles A. Lesburg, Donovon A. Adpressa, Shishi Lin, Santhosh Neelamkavil, Ping Liu, Jing Su, Laxminarayan G. Hegde, Janice D. Woodhouse, Robert Faltus, Tina Xiong, Paul J. Ciaccio, Jennifer Piesvaux, Karin M. Otte, Harold B. Wood, Matthew Kennedy, David Jonathan Bennett, Erin F. DiMauro, Matthew Fell, Peter H. Fuller
Abstract
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson’s disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.