Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor
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- 作者：Bryan K. Chan ; Anthony A. Estrada ; Huifen Chen ; John Atherall ; Charles Baker-Glenn ; Alan Beresford ; Daniel J. Burdick ; Mark Chambers ; Sara L. Dominguez ; Jason Drummond ; Andrew Gill ; Tracy Kleinheinz ; Claire E. Le Pichon ; Andrew D. Medhurst ; Xingrong Liu ; John G. Moffat ; Kevin Nash ; Kimberly Scearce-Levie ; Zejuan Sheng ; Daniel G. Shore ; Herv茅 Van de Po毛l ; Shuo Zhang ; Haitao Zhu ; Zachary K. Sweeney
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：4
- 期：1
- 页码：85-90
- 全文大小：306K
- 年卷期：v.4,no.1(January 10, 2013)
- ISSN：1948-5875
文摘
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.