We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.

我们描述了作为有效和选择性LRRK2抑制剂的5-取代-N-哒嗪基苯甲酰胺衍生物的发现和优化。广泛的SAR研究导致化合物18和23的鉴定，与18种其他激酶相比，它们具有良好的体外药代动力学特性和出色的选择性。两种化合物在血液和大脑中均显示出较高的未结合部分。化合物18被证明是脑渗透剂，化合物18在脑中的高未结合部分使其能够在CNS中发挥体内功效，其中在以5 mg / kg / h静脉输注后，在大鼠脑中观察到了LRRK2 Ser935磷酸化的显着抑制作用。