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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

Kannan Thirunavukkarasu, Bailin Tan, Craig A. Swearingen, Guilherme Rocha, Hai H. Bui, Denis J. McCann, Spencer B. Jones, Bryan H. Norman, Lance A. Pfeifer and Joy K. Saha
Journal of Pharmacology and Experimental Therapeutics October 2016, 359 (1) 207-214; DOI: https://doi.org/10.1124/jpet.116.234013
Kannan Thirunavukkarasu
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Bailin Tan
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Craig A. Swearingen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Guilherme Rocha
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Hai H. Bui
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Denis J. McCann
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Spencer B. Jones
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Bryan H. Norman
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Lance A. Pfeifer
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Joy K. Saha
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Abstract

Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenan-induced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate–induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.

Footnotes

    • Received April 29, 2016.
    • Accepted August 10, 2016.
  • dx.doi.org/10.1124/jpet.116.234013.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 359 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 359, Issue 1
1 Oct 2016
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Autotaxin Inhibitor for IBD and MS

Kannan Thirunavukkarasu, Bailin Tan, Craig A. Swearingen, Guilherme Rocha, Hai H. Bui, Denis J. McCann, Spencer B. Jones, Bryan H. Norman, Lance A. Pfeifer and Joy K. Saha
Journal of Pharmacology and Experimental Therapeutics October 1, 2016, 359 (1) 207-214; DOI: https://doi.org/10.1124/jpet.116.234013

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Autotaxin Inhibitor for IBD and MS

Kannan Thirunavukkarasu, Bailin Tan, Craig A. Swearingen, Guilherme Rocha, Hai H. Bui, Denis J. McCann, Spencer B. Jones, Bryan H. Norman, Lance A. Pfeifer and Joy K. Saha
Journal of Pharmacology and Experimental Therapeutics October 1, 2016, 359 (1) 207-214; DOI: https://doi.org/10.1124/jpet.116.234013
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