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Research ArticleNeuropharmacology

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587
Matthew J. Fell
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Christian Mirescu
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Kallol Basu
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Boonlert Cheewatrakoolpong
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Duane E. DeMong
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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J. Michael Ellis
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Lynn A. Hyde
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Yinghui Lin
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Carrie G. Markgraf
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Hong Mei
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Michael Miller
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Frederique M. Poulet
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Jack D. Scott
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Michelle D. Smith
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Zhizhang Yin
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Xiaoping Zhou
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Eric M. Parker
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Matthew E. Kennedy
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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John A. Morrow
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Abstract

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.

Footnotes

    • Received August 6, 2015.
    • Accepted September 24, 2015.
  • ↵1 M.J.F. and C.M. contributed equally to the writing of the manuscript.

  • dx.doi.org/10.1124/jpet.115.227587.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
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Research ArticleNeuropharmacology

MLi-2, a Potent and Selective Inhibitor of LRRK2

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587

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Research ArticleNeuropharmacology

MLi-2, a Potent and Selective Inhibitor of LRRK2

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587
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