| Autor: |
John Atherall, Bryan K. Chan, Tracy Kleinheinz, Daniel G. Shore, Andrew D. Medhurst, Huifen Chen, Haitao Zhu, Anthony A. Estrada, Sara L. Dominguez, Kimberly Scearce-Levie, Jason Drummond, Alan Beresford, Kevin M. Nash, Zejuan Sheng, Mark Stuart Chambers, Zachary Kevin Sweeney, Andrew Gill, Claire E. Le Pichon, Shuo Zhang, Charles Baker-Glenn, John Moffat, Hervé Van de Poël, Daniel J. Burdick, Xingrong Liu |
| Rok vydání: |
2012 |
| Předmět: |
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| Zdroj: |
ACS Medicinal Chemistry Letters. 4:85-90 |
| ISSN: |
1948-5875 |
| DOI: |
10.1021/ml3003007 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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