1415099-67-0Relevant articles and documents
Discovery of a highly selective, brain-penetrant aminopyrazole LRRK2 inhibitor
Chan, Bryan K.,Estrada, Anthony A.,Chen, Huifen,Atherall, John,Baker-Glenn, Charles,Beresford, Alan,Burdick, Daniel J.,Chambers, Mark,Dominguez, Sara L.,Drummond, Jason,Gill, Andrew,Kleinheinz, Tracy,Le Pichon, Claire E.,Medhurst, Andrew D.,Liu, Xingrong,Moffat, John G.,Nash, Kevin,Scearce-Levie, Kimberly,Sheng, Zejuan,Shore, Daniel G.,Van De Po?l, Hervé,Zhang, Shuo,Zhu, Haitao,Sweeney, Zachary K.
supporting information, p. 85 - 90 (2013/03/14)
The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs.
