Nemeth Edward F, Heaton William H, Miller Michael, Fox John, Balandrin Manuel F, Van Wagenen Bradford C, Colloton Mathew, Karbon William, Scherrer Jon, Shatzen Edward, Rishton Gilbert, Scully Sheila, Qi Meiying, Harris Robert, Lacey David, Martin David
Amgen, Inc., Thousand Oaks, CA 91320-1799, USA.
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+)) 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+) 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.
拟钙剂化合物可激活甲状旁腺细胞钙受体（CaR）并抑制甲状旁腺激素（PTH）分泌，目前正作为甲状旁腺功能亢进症的一种治疗方法进行实验研究。本报告描述了一种新型拟钙剂化合物盐酸西那卡塞的显著药效学特性，使用了多种测试系统。盐酸西那卡塞可增加表达人甲状旁腺CaR的人胚肾293细胞中细胞质钙（[Ca(2+)]i）的浓度。在存在0.5 mM细胞外钙的情况下，盐酸西那卡塞（EC(50) = 51 nM）以剂量和钙依赖性方式引起[Ca(2+)]i增加。同样，在存在0.5 mM细胞外钙的情况下，盐酸西那卡塞（IC(50) = 28 nM）使培养的牛甲状旁腺细胞分泌的PTH呈浓度依赖性降低。使用表达CaR的大鼠甲状腺髓样癌6 - 23细胞，盐酸西那卡塞（EC(50) = 34 nM）使降钙素分泌呈浓度依赖性增加。在大鼠体内研究表明，盐酸西那卡塞口服生物利用度良好，在1至36 mg/kg的剂量范围内显示出近似线性的药代动力学。此外，该化合物以剂量依赖性方式抑制血清PTH和血液离子钙（Ca(2+)）水平，并增加血清降钙素水平。西那卡塞降低血清PTH水平的效力比增加血清降钙素水平的效力高约30倍。西那卡塞的S - 对映体（S - AMG 073）在这些测定系统中的活性至少低75倍。目前的研究结果提供了令人信服的证据，表明盐酸西那卡塞是甲状旁腺CaR的强效和立体选择性激活剂，因此可能对甲状旁腺功能亢进症的治疗有益。
