Journal of Medicinal Chemistry p. 2983 - 2992 (2017)
Update date:2022-08-11
Topics:
Scott, Jack D.
DeMong, Duane E.
Greshock, Thomas J.
Basu, Kallol
Dai, Xing
Harris, Joel
Hruza, Alan
Li, Sarah W.
Lin, Sue-Ing
Liu, Hong
Macala, Megan K.
Hu, Zhiyong
Mei, Hong
Zhang, Honglu
Walsh, Paul
Poirier, Marc
Shi, Zhi-Cai
Xiao, Li
Agnihotri, Gautam
Baptista, Marco A. S.
Columbus, John
Fell, Matthew J.
Hyde, Lynn A.
Kuvelkar, Reshma
Lin, Yinghui
Mirescu, Christian
Morrow, John A.
Yin, Zhizhang
Zhang, Xiaoping
Zhou, Xiaoping
Chang, Ronald K.
Embrey, Mark W.
Sanders, John M.
Tiscia, Heather E.
Drolet, Robert E.
Kern, Jonathan T.
Sur, Sylvie M.
Renger, John J.
Bilodeau, Mark T.
Kennedy, Matthew E.
Parker, Eric M.
Stamford, Andrew W.
Nargund, Ravi
McCauley, John A.
Miller, Michael W.
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.
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