Nagano Nobuo, Nemeth Edward F
Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd., Gunma.
J Pharmacol Sci. 2005 Mar;97(3):355-60. doi: 10.1254/jphs.fmj04007x6. Epub 2005 Mar 17.
Circulating levels of calcium ion (Ca(2+)) are maintained within a narrow physiological range mainly by the action of parathyroid hormone (PTH) secreted from parathyroid cells. Parathyroid cells can sense small fluctuations in plasma Ca(2+) levels by virtue of a cell surface Ca(2+) receptor (CaR) that belongs to the superfamily of G-protein-coupled receptors. Calcimimetics are positive allosteric modulators that activate the CaR on parathyroid cells and thereby immediately suppress PTH secretion. Pre-clinical studies with NPS R-568, a first generation calcimimetic compound, have demonstrated that daily oral administration inhibits the elevation of plasma PTH levels and parathyroid gland hyperplasia and ameliorates impaired bone qualities in rats with chronic renal insufficiency. The results of clinical trials with cinacalcet hydrochloride, a second generation calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum calcium x phosphorus product levels, a hallmark of an increased risk for cardiovascular death in dialysis patients with end-stage renal disease (ESRD). Thus, calcimimetics have considerable potential as an innovative medical approach to manage secondary hyperparathyroidism associated with ESRD. Indeed, cinacalcet hydrochloride has been approved in several countries and is the first positive allosteric modulator of any G protein-coupled receptor to reach the market.
钙离子(Ca(2+))的循环水平主要通过甲状旁腺细胞分泌的甲状旁腺激素(PTH)的作用维持在狭窄的生理范围内。甲状旁腺细胞可借助属于G蛋白偶联受体超家族的细胞表面Ca(2+)受体(CaR)感知血浆Ca(2+)水平的微小波动。拟钙剂是正变构调节剂,可激活甲状旁腺细胞上的CaR,从而立即抑制PTH分泌。对第一代拟钙剂化合物NPS R-568的临床前研究表明,每日口服给药可抑制慢性肾功能不全大鼠血浆PTH水平升高和甲状旁腺增生,并改善受损的骨质。对第二代拟钙剂化合物盐酸西那卡塞的临床试验结果表明,拟钙剂不仅对血清PTH水平有降低作用,而且对血清钙磷乘积水平也有降低作用,这是终末期肾病(ESRD)透析患者心血管死亡风险增加的一个标志。因此,拟钙剂作为一种治疗与ESRD相关的继发性甲状旁腺功能亢进的创新医学方法具有相当大的潜力。事实上,盐酸西那卡塞已在多个国家获批,是首个上市的任何G蛋白偶联受体的正变构调节剂。