Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl

J Pharmacol Exp Ther. 2004 Feb;308(2):627-35. doi: 10.1124/jpet.103.057273. Epub 2003 Oct 30.


Calcimimetic compounds, which activate the parathyroid cell Ca(2+) 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 Ca(2+) ([Ca(2+)](i)) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC(50) = 51 nM) in the presence of 0.5 mM extracellular Ca(2+) elicited increases in [Ca(2+)](i) in a dose- and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca(2+), cinacalcet HCl (IC(50) = 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 (EC(50) = 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 Ca(2+) 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.

MeSH terms

  • Animals
  • Calcitonin / blood
  • Calcitonin / metabolism*
  • Calcium / blood
  • Calcium-Binding Proteins / metabolism
  • Cells, Cultured
  • Cinacalcet
  • Humans
  • Male
  • Naphthalenes / pharmacokinetics
  • Naphthalenes / pharmacology*
  • Parathyroid Glands / drug effects*
  • Parathyroid Glands / metabolism
  • Parathyroid Hormone / blood
  • Parathyroid Hormone / metabolism*
  • Phosphorus / blood
  • Rats
  • Rats, Sprague-Dawley


  • Calcium-Binding Proteins
  • Naphthalenes
  • Parathyroid Hormone
  • Phosphorus
  • Calcitonin
  • Calcium
  • Cinacalcet