Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration.

用小分子抑制LRRK2激酶活性已成为帕金森氏病的潜在新治疗方法。在本文中，我们公开了发现4-乙氧基-7 H-吡咯并[2,3- d ]嘧啶-2-胺系列作为有效的LRRK2抑制剂的作用，这些抑制剂是通过针对激酶的固定筛选确定的。优化的物理化学性质，并导致化合物的发现激酶选择性7，其显示强效的体外LRRK2的抑制激酶活性，良好的物理化学性质和激酶选择性横跨激酶组。此外，化合物7能够渗入CNS和体内 药理学研究显示，口服给药后，大鼠（30和100 mg / kg）和小鼠（45 mg / kg）的大脑中Ser935磷酸化都有明显的抑制作用。