Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl
Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl
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DOI：
10.1124/jpet.103.057273
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发表时间：
2004-02-01
影响因子：
3.5
通讯作者：
Martin, D
中科院分区：
文献类型：
--
作者：
Nemeth, EF;Heaton, WH;Martin, D
激活甲状旁腺细胞Ca 2+受体（CaR）并抑制甲状旁腺激素（PTH）分泌的拟钙化合物作为甲状旁腺机能亢进的治疗正在实验研究中。本报告介绍了显着的药效学特性，使用几个测试系统，一种新的拟钙化合物，盐酸西那卡塞。盐酸西那卡塞增加了表达人甲状旁腺CaR的人胚肾293细胞中细胞质Ca 2+（[Ca 2 +]（i））的浓度。在存在0.5 mM细胞外Ca 2+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。类似地，在存在0.5 mM细胞外Ca 2+的情况下，西那卡塞盐酸盐（IC 50 = 28 nM）使培养的牛甲状旁腺细胞的PTH分泌产生浓度依赖性降低。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）产生降钙素分泌的浓度依赖性增加。大鼠体内研究表明，盐酸西那卡塞具有口服生物利用度，在1 - 36 mg/kg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和血液离子化Ca 2+水平并增加血清降钙素水平。西那卡塞降低血清PTH水平的效力是增加血清降钙素水平的约30倍。西那卡塞的S-对映异构体（S-AMG 073）在这些试验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，证明盐酸西那卡塞是甲状旁腺CaR的有效和立体选择性激活剂，因此可能有益于甲状旁腺功能亢进的治疗。
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.