| Literature DB >> 28245354 |
Jack D Scott1, Duane E DeMong2, Thomas J Greshock3, Kallol Basu4, Xing Dai1, Joel Harris1, Alan Hruza1, Sarah W Li3, Sue-Ing Lin1, Hong Liu1, Megan K Macala1, Zhiyong Hu1, Hong Mei1, Honglu Zhang1, Paul Walsh4, Marc Poirier1, Zhi-Cai Shi1, Li Xiao1, Gautam Agnihotri1, Marco A S Baptista1, John Columbus2, Matthew J Fell2, Lynn A Hyde1, Reshma Kuvelkar1, Yinghui Lin1, Christian Mirescu2, John A Morrow1, Zhizhang Yin1, Xiaoping Zhang1, Xiaoping Zhou1, Ronald K Chang3, Mark W Embrey3, John M Sanders3, Heather E Tiscia3, Robert E Drolet3, Jonathan T Kern3, Sylvie M Sur3, John J Renger3, Mark T Bilodeau3, Matthew E Kennedy2, Eric M Parker1, Andrew W Stamford1, Ravi Nargund1, John A McCauley3, Michael W Miller1.
Abstract
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.Entities:
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Year: 2017 PMID： 28245354 DOI： 10.1021/acs.jmedchem.7b00045
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446