Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity

被引：111

作者：

Scott, Jack D. ^{[1
,5
]}

DeMong, Duane E. ^{[2
]}

Greshock, Thomas J. ^{[3
]}

Basu, Kallol ^{[4
]}

Dai, Xing ^{[1
]}

Harris, Joel ^{[1
]}

Hruza, Alan ^{[1
]}

Li, Sarah W. ^{[3
]}

Lin, Sue-Ing ^{[1
]}

Liu, Hong ^{[1
]}

Macala, Megan K. ^{[1
,6
]}

Hu, Zhiyong ^{[1
]}

Mei, Hong ^{[1
]}

Zhang, Honglu ^{[1
]}

Walsh, Paul ^{[4
]}

Poirier, Marc ^{[1
]}

Shi, Zhi-Cai ^{[1
]}

Xiao, Li ^{[1
]}

Agnihotri, Gautam ^{[1
,7
]}

Baptista, Marco A. S. ^{[1
,8
]}

Columbus, John ^{[2
,9
]}

Fell, Matthew J. ^{[2
]}

Hyde, Lynn A. ^{[1
]}

Kuvelkar, Reshma ^{[1
]}

Lin, Yinghui ^{[1
]}

Mirescu, Christian ^{[2
]}

Morrow, John A. ^{[1
]}

Yin, Zhizhang ^{[1
]}

Zhang, Xiaoping ^{[1
]}

Zhou, Xiaoping ^{[1
]}

Chang, Ronald K. ^{[3
]}

Embrey, Mark W. ^{[3
]}

Sanders, John M. ^{[3
]}

Tiscia, Heather E. ^{[3
]}

Drolet, Robert E. ^{[3
]}

Kern, Jonathan T. ^{[1
,3
,11
]}

Sur, Sylvie M. ^{[3
]}

Renger, John J. ^{[3
,12
]}

Bilodeau, Mark T. ^{[3
,13
]}

Kennedy, Matthew E. ^{[2
]}

Parker, Eric M. ^{[1
]}

Stamford, Andrew W. ^{[1
]}

Nargund, Ravi ^{[1
]}

McCauley, John A. ^{[3
,10
]}

Miller, Michael W. ^{[1
]}

机构：

[1] Merck & Co Inc, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, 33 Ave Louis Pasteur, Boston, MA 02115 USA

[3] Merck & Co Inc, 770 Sumneytown Pike, West Point, PA 19486 USA

[4] Merck & Co Inc, 126 East Lincoln Ave, Rahway, NJ 07065 USA

[5] HB Fuller, Vadnais Hts, MN 55110 USA

[6] AECOM, Pittsburgh, PA 15219 USA

[7] WuXi AppTec, Plainsboro, NJ 08536 USA

[8] Michael J Fox Fdn, New York, NY 10018 USA

[9] Leidos Biomed Res Inc, Frederick, MD 21701 USA

[10] IOmet Pharm, Edinburgh EH16 4UX, Midlothian, Scotland

[11] AbbVie, N Chicago, IL 60064 USA

[12] Purdue Pharma, Stamford, CT 06901 USA

[13] Tarveda Therapeut Watertown, Watertown, MA 02472 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 07期

关键词：

ONSET PARKINSONS-DISEASE; AUTOSOMAL-DOMINANT PARKINSONISM; HIGHLY POTENT; MUTATIONS; PREDICTION; PENETRANT; COMPOUND; SAFETY; GENE;

D O I：

10.1021/acs.jmedchem.7b00045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

引用

页码：2983 / 2992

页数：10

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