Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2013 Apr 1;23(7):1974-7. doi: 10.1016/j.bmcl.2013.02.041. Epub 2013 Feb 15.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
富含亮氨酸重复激酶 2（LRRK2）的突变与家族性帕金森病（PD）有关。该复合蛋白的激酶活性通过致病突变而增加。因此，抑制 LRRK2 的激酶活性已成为治疗 PD 的一种有前途的方法。在此，我们报告了一系列 4-烷基氨基-7-芳基-3-氰基喹啉的研究结果，这些化合物对野生型和 G2019S 突变型 LRRK2 均具有激酶抑制活性。在生化和细胞测定中均测定了活性。进一步在体内药效学研究中评价了化合物 14，发现其经口服给药后可显著抑制 Ser935 磷酸化。
