Candito David A, Simov Vladimir, Gulati Anmol, Kattar Solomon, Chau Ryan W, Lapointe Blair T, Methot Joey L, DeMong Duane E, Graham Thomas H, Kurukulasuriya Ravi, Keylor Mitchell H, Tong Ling, Morriello Gregori J, Acton John J, Pio Barbara, Liu Weiguo, Scott Jack D, Ardolino Michael J, Martinot Theodore A, Maddess Matthew L, Yan Xin, Gunaydin Hakan, Palte Rachel L, McMinn Spencer E, Nogle Lisa, Yu Hongshi, Minnihan Ellen C, Lesburg Charles A, Liu Ping, Su Jing, Hegde Laxminarayan G, Moy Lily Y, Woodhouse Janice D, Faltus Robert, Xiong Tina, Ciaccio Paul, Piesvaux Jennifer A, Otte Karin M, Kennedy Matthew E, Bennett David Jonathan, DiMauro Erin F, Fell Matthew J, Neelamkavil Santhosh, Wood Harold B, Fuller Peter H, Ellis J Michael
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts02115, United States.
Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey07033, United States.
J Med Chem. 2022 Dec 22;65(24):16801-16817. doi: 10.1021/acs.jmedchem.2c01605. Epub 2022 Dec 7.
Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp-sp cross-coupling technologies. This resulted in the discovery of a unique sp-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, , demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.
抑制富含亮氨酸重复激酶2（LRRK2）的激酶活性是一种有遗传学依据、化学上易于处理且可能改变疾病进程的治疗帕金森病的机制。在此，我们描述了一系列新型强效、选择性、可穿透中枢神经系统（CNS）的1-杂芳基-1-吲唑I型（ATP竞争性）LRRK2抑制剂的优化过程。通过基于结构的药物设计与由sp-sp交叉偶联技术实现的平行药物化学相结合，将I型ATP竞争性激酶的物理化学性质与CNS类药物性质整合在一起。这导致发现了一种独特的富含sp的螺腈基序，其赋予了非凡的效力、药代动力学和良好的CNS类药物性质。先导化合物在人外周血单核细胞中表现出卓越的靶向效力、出色的脱靶激酶选择性以及在大鼠体内良好的脑内暴露，最终实现了较低的预估人体剂量和良好的临床前安全性，这为开展临床前候选药物启用研究提供了依据。
