1182917-01-6Relevant 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.
, p. 85 - 90 (2013)
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.
9-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE
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Paragraph 54; 67-68, (2020/06/19)
In its many embodiments, the present invention provides certain 9-substituted amino triazolo quinazoline compounds of the structural Formula (I): (I), and pharmaceutically acceptable salts thereof, wherein, ring A, R1 and R2 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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Paragraph 0395, (2017/03/28)
The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
