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Research ArticleDrug Discovery and Translational Medicine

Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion

Charles Henley III, Yuhua Yang, James Davis, Jenny Ying Lin Lu, Sean Morony, Wei Fan, Monica Florio, Banghua Sun, Edward Shatzen, James K. Pretorius, William G. Richards, David J. St. Jean Jr, Christopher Fotsch and Jeff D. Reagan
Journal of Pharmacology and Experimental Therapeutics June 2011, 337 (3) 681-691; DOI: https://doi.org/10.1124/jpet.110.178681
Charles Henley III
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Yuhua Yang
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James Davis
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Jenny Ying Lin Lu
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Sean Morony
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Wei Fan
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Monica Florio
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Banghua Sun
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Edward Shatzen
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James K. Pretorius
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William G. Richards
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David J. St. Jean Jr
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Christopher Fotsch
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Jeff D. Reagan
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Abstract

Calcimimetics are positive allosteric modulators to the calcium-sensing receptor (CaSR). Activation of the CaSR inhibits the secretion of parathyroid hormone (PTH), stimulates the secretion of calcitonin, and decreases serum calcium (Ca2+). Cinacalcet, a second-generation calcimimetic, is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism. A calcimimetic that displays increased separation of PTH versus Ca2+ lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population. Toward this end, we developed a third-generation calcimimetic, determined the molecular pharmacological properties of it using an operation model of allosteric modulation/agonism, and measured the compound effects on PTH, serum ionized Ca2+, and calcitonin levels in 5/6 nephrectomized rats. We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia. Furthermore, our third-generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine (R-568), a first-generation calcimimetic. These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion.

Footnotes

  • This research was wholly funded by Amgen, Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.178681.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CaSR
    calcium-sensing receptor
    hCaSR
    human CaSR
    CKD
    chronic kidney disease
    ESRD
    end-stage renal disease
    FLIPR
    fluorescent imaging plate reader
    IP
    inositol phosphate
    PTH
    parathyroid hormone
    Nx
    nephrectomized
    SHPT
    secondary hyperparathyroidism
    R-568
    3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine
    HEK
    human embryonic kidney
    DMEM
    Dulbecco's modified Eagle's medium
    DMSO
    dimethyl sulfoxide
    HBSS
    Hanks' balanced salt solution
    BSA
    bovine serum albumin
    ELISA
    enzyme-linked immunosorbent assay
    ERK
    extracellular signal-regulated kinase.

  • Received December 28, 2010.
  • Accepted March 16, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion

Charles Henley, Yuhua Yang, James Davis, Jenny Ying Lin Lu, Sean Morony, Wei Fan, Monica Florio, Banghua Sun, Edward Shatzen, James K. Pretorius, William G. Richards, David J. St. Jean, Christopher Fotsch and Jeff D. Reagan
Journal of Pharmacology and Experimental Therapeutics June 1, 2011, 337 (3) 681-691; DOI: https://doi.org/10.1124/jpet.110.178681

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Research ArticleDrug Discovery and Translational Medicine

Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion

Charles Henley, Yuhua Yang, James Davis, Jenny Ying Lin Lu, Sean Morony, Wei Fan, Monica Florio, Banghua Sun, Edward Shatzen, James K. Pretorius, William G. Richards, David J. St. Jean, Christopher Fotsch and Jeff D. Reagan
Journal of Pharmacology and Experimental Therapeutics June 1, 2011, 337 (3) 681-691; DOI: https://doi.org/10.1124/jpet.110.178681
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