@article {Nemeth627, author = {Edward F. Nemeth and William H. Heaton and Michael Miller and John Fox and Manuel F. Balandrin and Bradford C. Van Wagenen and Mathew Colloton and William Karbon and Jon Scherrer and Edward Shatzen and Gilbert Rishton and Sheila Scully and Meiying Qi and Robert Harris and David Lacey and David Martin}, title = {Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl}, volume = {308}, number = {2}, pages = {627--635}, year = {2004}, doi = {10.1124/jpet.103.057273}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/308/2/627}, eprint = {https://jpet.aspetjournals.org/content/308/2/627.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }