Journal of medicinal chemistry · 2026
Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson's Disease.
СтатьяНазвание и аннотация: Перевод в очереди
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Yu Elsie C, Zhou Hua, Yan Xin, Logan Kaitlyn M, Li Derun, Gulati Anmol, Poremba Kelsey E, Ardolino Michael J, Su Jing, Xiao Dong, Palte Rachel L, McMinn Spencer E, Nogle Lisa M, Adpressa Donovon A, Burgess Samantha A, Xiong Tina, Otte Karin M, Chobanian Harry R, Bass Alan, Lee Susi, Pearson Kara, Messina Eric, Parisi Michael, Barnum John, Sobol Zhanna, Ciaccio Paul J, DiMauro Erin F, Fell Matthew J, Fuller Peter H
Аннотация
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 7, which was profiled extensively before it was determined to be clastogenic, which halted its progression. Parallel optimization of kinome selectivity and PXR activation through structure- and property-based drug design resulted in the discovery of the lead macrocycle compound 12. This macrocycle boasts a remarkably low projected human QD dose, is nongenotoxic, and achieved encouraging brain penetration in early preclinical models.