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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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Article Information

vol. 355 no. 3 397-409
DOI 
https://doi.org/10.1124/jpet.115.227587
PubMed 
26407721

Published By 
American Society for Pharmacology and Experimental Therapeutics
Print ISSN 
0022-3565
Online ISSN 
1521-0103
History 
  • Received August 6, 2015
  • Accepted September 24, 2015
  • Published online October 29, 2015.

Article Versions

  • Earlier version (September 25, 2015 - 10:16).
  • You are viewing the most recent version of this article.
Copyright & Usage 
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics

Author Information

  1. Matthew J. Fell1,
  2. Christian Mirescu1,
  3. Kallol Basu,
  4. Boonlert Cheewatrakoolpong,
  5. Duane E. DeMong,
  6. J. Michael Ellis,
  7. Lynn A. Hyde,
  8. Yinghui Lin,
  9. Carrie G. Markgraf,
  10. Hong Mei,
  11. Michael Miller,
  12. Frederique M. Poulet,
  13. Jack D. Scott,
  14. Michelle D. Smith,
  15. Zhizhang Yin,
  16. Xiaoping Zhou,
  17. Eric M. Parker,
  18. Matthew E. Kennedy, and
  19. John A. Morrow
  1. 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.)
  1. Address correspondence to:
    Dr. Matthew J. Fell, Neuroscience Early Discovery, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, 02115. matthew.fell{at}merck.com
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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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