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Research ArticleDrug Discovery and Translational Medicine

Altering Metabolic Profiles of Drugs by Precision Deuteration: Reducing Mechanism-Based Inhibition of CYP2D6 by Paroxetine

Vinita Uttamsingh, Richard Gallegos, Julie F. Liu, Scott L. Harbeson, Gary W. Bridson, Changfu Cheng, David S. Wells, Philip B. Graham, Robert Zelle and Roger Tung
Journal of Pharmacology and Experimental Therapeutics July 2015, 354 (1) 43-54; DOI: https://doi.org/10.1124/jpet.115.223768
Vinita Uttamsingh
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Richard Gallegos
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Julie F. Liu
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Scott L. Harbeson
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Gary W. Bridson
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Changfu Cheng
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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David S. Wells
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Philip B. Graham
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Robert Zelle
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Roger Tung
Concert Pharmaceuticals, Inc., Lexington, Massachusetts
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Abstract

Selective deuterium substitution as a means of ameliorating clinically relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chemical entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 was metabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metabolism profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metabolism profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.

Footnotes

    • Received February 24, 2015.
    • Accepted April 15, 2015.
  • C.C., D.S.W., and R.Z. are former employees of Concert Pharmaceuticals, Inc.

  • dx.doi.org/10.1124/jpet.115.223768.

  • ↵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: 354 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 354, Issue 1
1 Jul 2015
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Research ArticleDrug Discovery and Translational Medicine

Altering Metabolic Profiles of Drugs with Precision Deuteration

Vinita Uttamsingh, Richard Gallegos, Julie F. Liu, Scott L. Harbeson, Gary W. Bridson, Changfu Cheng, David S. Wells, Philip B. Graham, Robert Zelle and Roger Tung
Journal of Pharmacology and Experimental Therapeutics July 1, 2015, 354 (1) 43-54; DOI: https://doi.org/10.1124/jpet.115.223768

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Research ArticleDrug Discovery and Translational Medicine

Altering Metabolic Profiles of Drugs with Precision Deuteration

Vinita Uttamsingh, Richard Gallegos, Julie F. Liu, Scott L. Harbeson, Gary W. Bridson, Changfu Cheng, David S. Wells, Philip B. Graham, Robert Zelle and Roger Tung
Journal of Pharmacology and Experimental Therapeutics July 1, 2015, 354 (1) 43-54; DOI: https://doi.org/10.1124/jpet.115.223768
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