PT  - JOURNAL ARTICLE
AU  - Fell, Matthew J.
AU  - Mirescu, Christian
AU  - Basu, Kallol
AU  - Cheewatrakoolpong, Boonlert
AU  - DeMong, Duane E.
AU  - Ellis, J. Michael
AU  - Hyde, Lynn A.
AU  - Lin, Yinghui
AU  - Markgraf, Carrie G.
AU  - Mei, Hong
AU  - Miller, Michael
AU  - Poulet, Frederique M.
AU  - Scott, Jack D.
AU  - Smith, Michelle D.
AU  - Yin, Zhizhang
AU  - Zhou, Xiaoping
AU  - Parker, Eric M.
AU  - Kennedy, Matthew E.
AU  - Morrow, John A.
TI  - MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition
AID  - 10.1124/jpet.115.227587
DP  - 2015 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 397--409
VI  - 355
IP  - 3
4099  - http://jpet.aspetjournals.org/content/355/3/397.short
4100  - http://jpet.aspetjournals.org/content/355/3/397.full
SO  - J Pharmacol Exp Ther2015 Dec 01; 355
AB  - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson’s disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dose-dependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models.