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

• Published in: Journal of medicinal chemistry Vol. 60; no. 7; pp. 2983 - 2992
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13-04-2017
• Subjects: Animals; Brain - metabolism; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Humans; Indazoles - administration & dosage; Indazoles - chemistry; Indazoles - pharmacokinetics; Indazoles - pharmacology; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - antagonists & inhibitors; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Male; Molecular Docking Simulation; Parkinson Disease - drug therapy; Parkinson Disease - enzymology; Rats; Rats, Wistar
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00045

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.