作者
Solomon D. Kattar,Anmol Gulati,Kaila A. Margrey,Mitchell H. Keylor,Michael J. Ardolino,Xin Yan,Rebecca Johnson,R.L. Palte,Spencer E. McMinn,Lisa Nogle,Jing Su,Dong Xiao,Jennifer Piesvaux,S. Lee,Laxminarayan G. Hegde,Janice D Woodhouse,Robert Faltus,Lily Y. Moy,Tina Xiong,Paul J. Ciaccio,Kara Pearson,Mayankbhai Patel,Karin Otte,Cheryl E. G. Leyns,Matthew Kennedy,David Jonathan Bennett,Erin F. DiMauro,Matthew Fell,Peter H. Fuller
摘要
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. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.