Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl.

Abstract

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.

• Authors: 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, David Martin
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 308 Issue 2 Pg. 627-35 (Feb 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14593085 (Publication Type: Journal Article)

Chemical References

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

Topics

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