Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl.
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.
Nemeth
Edward F
EF
Amgen, Inc., Thousand Oaks, CA 91320-1799, USA.
Heaton
William H
WH
Miller
Michael
M
Fox
John
J
Balandrin
Manuel F
MF
Van Wagenen
Bradford C
BC
Colloton
Mathew
M
Karbon
William
W
Scherrer
Jon
J
Shatzen
Edward
E
Rishton
Gilbert
G
Scully
Sheila
S
Qi
Meiying
M
Harris
Robert
R
Lacey
David
D
Martin
David
D
D000818:Animals; D002116:Calcitonin / Q000097:blood / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000069449:Cinacalcet; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism*; D010758:Phosphorus / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D002135:Calcium-Binding Proteins; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010758:Phosphorus; D002116:Calcitonin; D002118:Calcium; D000069449:Cinacalcet