389606-74-0Relevant articles and documents
PYRAZOLE AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS FOR USE IN THE TREATMENT OF PARKINSON'S DISEASE
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Page/Page column 44, (2013/11/19)
Compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein X, R1, R2, R3 and A are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease
Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling
Chen, Huifen,Chan, Bryan K.,Drummond, Jason,Estrada, Anthony A.,Gunzner-Toste, Janet,Liu, Xingrong,Liu, Yichin,Moffat, John,Shore, Daniel,Sweeney, Zachary K.,Tran, Thuy,Wang, Shumei,Zhao, Guiling,Zhu, Haitao,Burdick, Daniel J.
experimental part, p. 5536 - 5545 (2012/08/28)
Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for the development of Parkinson's disease (PD). Potent and selective small molecules capable of inhibiting the kinase activity of LRRK2 will be important tools for establishing a link between the kinase activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal structures, a LRRK2 homology model was developed that provided robust guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors. Through a combination of molecular modeling, sequence analysis, and matched molecular pair (MMP) activity cliff analysis, a potent and selective lead inhibitor was discovered. The selectivity of this compound could be understood using the LRRK2 homology model, and application of this learning to a series of 2,4-diaminopyrimidine inhibitors in a scaffold hopping exercise led to the identification of highly potent and selective LRRK2 inhibitors that were also brain penetrable.
