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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl

Edward F. Nemeth, William H. Heaton, Michael Miller, John Fox, Manuel F. Balandrin, Bradford C. Van Wagenen, Mathew Colloton, William Karbon, Jon Scherrer, Edward Shatzen, Gilbert Rishton, Sheila Scully, Meiying Qi, Robert Harris, David Lacey and David Martin
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 627-635; DOI: https://doi.org/10.1124/jpet.103.057273
Edward F. Nemeth
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William H. Heaton
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Michael Miller
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John Fox
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Manuel F. Balandrin
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Bradford C. Van Wagenen
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Mathew Colloton
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William Karbon
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Jon Scherrer
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Edward Shatzen
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Gilbert Rishton
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Sheila Scully
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Meiying Qi
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Robert Harris
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David Lacey
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David Martin
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Abstract

Calcimimetic compounds, which activate the parathyroid cell Ca2+ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca2+ ([Ca2+]i) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC50 = 51 nM) in the presence of 0.5 mM extracellular Ca2+ elicited increases in [Ca2+]i in a dose- and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca2+, cinacalcet HCl (IC50 = 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC50 = 34 nM) produced a concentration-dependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca2+ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

Footnotes

  • DOI: 10.1124/jpet.103.057273.

  • ABBREVIATIONS: PTH, parathyroid hormone; CaR, calcium sensing receptor; HPT, hyperparathyroidism; HEK, human embryonic kidney; [Ca2+]i, cytoplasmic calcium concentration; MTC, medullary thyroid carcinoma; DMSO, dimethyl sulfoxide; NPS R-568, (R)-N-(3-methoxy-α-phenylethyl)-2-(2′-chlorophenyl)-1-propylamine hydrochloride.

    • Received July 22, 2003.
    • Accepted October 23, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl

Edward F. Nemeth, William H. Heaton, Michael Miller, John Fox, Manuel F. Balandrin, Bradford C. Van Wagenen, Mathew Colloton, William Karbon, Jon Scherrer, Edward Shatzen, Gilbert Rishton, Sheila Scully, Meiying Qi, Robert Harris, David Lacey and David Martin
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 627-635; DOI: https://doi.org/10.1124/jpet.103.057273

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Research ArticleENDOCRINE AND REPRODUCTIVE

Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl

Edward F. Nemeth, William H. Heaton, Michael Miller, John Fox, Manuel F. Balandrin, Bradford C. Van Wagenen, Mathew Colloton, William Karbon, Jon Scherrer, Edward Shatzen, Gilbert Rishton, Sheila Scully, Meiying Qi, Robert Harris, David Lacey and David Martin
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 627-635; DOI: https://doi.org/10.1124/jpet.103.057273
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