Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl

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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.