CaSR ( EC50 = 2.8 μM )

体外活性：AMG-073代表了一类用于治疗甲状旁腺功能亢进症的新型化合物，称为拟钙剂，它通过增加甲状旁腺钙敏感受体（CaR）对细胞外钙的敏感性来减少甲状旁腺激素（PTH）的合成和分泌。 AMG-073 作为继发性甲状旁腺功能亢进症的治疗方法具有潜在优势，因为它模仿细胞外钙的作用来抑制 PTH 分泌，即使存在高磷血症，也不会导致高钙血症和/或高磷血症的风险。 AMG-073 在表达 CaSR 的人胚胎肾细胞中产生浓度依赖性的细胞质钙增加。在牛甲状旁腺细胞和含有 0.5 mM 钙的缓冲液中，AMG 073 (3 nM – 1 μM) 会产生浓度依赖性的 PTH 水平降低，IC50 为 27 nM。

AMG-073以1、3、10和30mg/kg的剂量溶解于20%磺丁基醚β-环糊精钠中，口服给予正常大鼠，给药后1至4小时内PTH水平产生显着的剂量依赖性降低。与对照组相比，8 小时后，10 毫克/千克和 30 毫克/千克剂量的 AMG-073 使 PTH 水平显着降低，并在 24 小时后消失。分别口服 AMG-073 3、10 和 30 mg/kg 后 4、8 和 24 小时，观察到血清钙水平显着剂量依赖性降低。仅在最高剂量的 AMG-073 下观察到血清磷水平短暂降低。此外，在大鼠中使用 AMG-073 40 mg/kg 观察到与 PTH 抑制平行的降钙素水平升高。与正常大鼠一样，口服 AMG-073 后，6 只肾切除大鼠中有 5 只观察到 PTH 和钙水平快速剂量依赖性降低。此外，与对照组相比，口服 5 和 10 mg/kg AMG-073 4 周可显着降低甲状旁腺重量。

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与赋形剂治疗的5/6肾切除大鼠相比，给予西那卡塞HCl（5或10mg/kg）显著减少了PCNA阳性细胞的数量，并降低了甲状旁腺重量。盐酸西那卡塞处理或载体处理的动物的细胞凋亡没有差异。与赋形剂处理的对照组相比，盐酸西那卡塞处理的动物血清PTH和血液离子钙水平降低。 结论：这些结果证实了之前的工作，表明钙样药物可以减轻亚全肾切除大鼠甲状旁腺增生的进展，将早期的观察扩展到现在包括盐酸西那卡塞。这些结果支持CaR在调节甲状旁腺细胞增殖中的作用。因此，盐酸西那卡塞可能是一种改善继发性HPT管理的新疗法[1]

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钙模拟物，如cinacalcet（Cin），增加了CaR对Ca的敏感性。Cin对UCa的影响是复杂的，难以预测。我们测试了Cin会改变尿（U）Ca和磷酸氢钙（CaHPO（4））和草酸钙（CaOx）过饱和度的假设。GHS或对照组大鼠喂食正常钙饮食（0.6%钙）28天，最后14天在每组一半的饮食中添加Cin（30mg/kg/24小时）。然后重复该方案，同时给大鼠喂食低钙（0.02%Ca）饮食。我们发现，Cin导致循环甲状旁腺激素显著降低，血清钙适度降低。当GHS大鼠喂食正常钙饮食时，Cin不会改变UCa，但当喂食低钙饮食时会降低UCa。然而，Cin并没有改变两种饮食中CaOx或CaHPO（4）的U过饱和度。如果这些在GHS大鼠中的发现可以在人类中得到证实，则表明Cin不是治疗人类特发性高钙尿症及其结石形成的有效药物[2]。

在转染了hCaSR和6×TRE荧光素酶报告系统的CHO细胞中评估了这些化合物。12随着钙浓度的增加，对化合物进行了剂量反应测试。正变构调节剂浓度的增加导致hCaSR钙反应的剂量成比例向左偏移。本文中所示的值对应于2mM钙的EC50。然后在体内测试最具活性的化合物降低正常大鼠PTH水平的能力。我们的两个起始点R-568和芬地林分别在80和1000 nM时具有活性，并产生了在60 nM时活性的化合物46Cinacalcet在该测定中的浓度为80 nM。[PMID:23465611]https://pubmed.ncbi.nlm.nih.gov/23465611/

The Apoptag System measures nuclear DNA fragmentation in situ to identify apoptosis in parathyroid glands from 5/6 nephrectomized or sham rats treated with Cinacalcet HCl (10 mg/kg) or vehicle. In summary, after being treated with vehicle or cinacalcet HCl, parathyroid gland sections from the animals are digested using 20 μg/mL proteinase K in 0.1 mol/L PBS at room temperature for 15 minutes.To block endogenous peroxidase, the samples are then incubated with 3% hydrogen peroxide/methanol for 5 minutes. To label exposed 3′-OH DNA ends with digoxigenin-tagged nucleotides, sections are incubated with terminal deoxynucleotidyl transferase (TdT) for 1 hour at 37°C. The immunoperoxidase method finds DNA that has been labeled with digoxigenin. The nuclei of apoptotic cells are stained brown, and sections are created using 3,3′-diaminobenzidine (DAB). When TdT is replaced with distilled water, the specificity for apoptosis is confirmed using negative staining.

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Cinacalcet HCl dosing for 4 weeks [1]
Starting 6 weeks postsurgery, 5/6 nephrectomized (N = 35) and sham (N = 18) animals received orally either vehicle (20% captisol in water) (mL/kg) or Cinacalcet HCl (1, 5, or 10 mg/kg) for 4 weeks. Sampling for the determination of serum PTH and serum chemistries after the initiation of cinacalcet HCl treatment began at the 8-week time point (see Figures 4 and 5 ).

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Apoptosis [2]
To identify apoptosis in parathyroid glands from 5/6 nephrectomized or sham rats treated with vehicle [phosphate-buffered saline (PBS)] or Cinacalcet HCl (10 mg/kg), nuclear DNA fragmentation was measured in situ using the Apoptag System. Briefly, parathyroid gland sections from animals treated with vehicle or cinacalcet HCl were digested with 20 μg/mL proteinase K in 0.1 mol/L PBS at room temperature for 15 minutes and incubated with 3% hydrogen peroxide/methanol for 5 minutes to block endogenous peroxidase. Sections were incubated for 1 hour at 37°C with terminal deoxynucleotidyl transferase (TdT) to label exposed 3′-OH DNA ends with digoxigenin-tagged nucleotides. Digoxigenin-labeled DNA was detected by the immunoperoxidase method. Sections were developed with 3,3′-diaminobenzidine (DAB), and the nuclei of apoptotic cells were stained brown. The specificity for apoptosis was verified by negative staining when distilled water was substituted for TdT.
Fourteen 67th generation female GHS rats and 14 female Sprague–Dawley Ctl rats, initially weighing on average 238 g, were placed in metabolic cages. From days 1 to 14, each rat in each group was fed 13 g/day of a NCD (0.6% Ca and 0.65% P, Harlan Teklad, Madison, WI, USA). We have previously shown that rats of this size completely consume this amount of diet on a daily basis.15, 17, 18, 19, 20 During the last 5 days of this period (day 10–14), five successive 24-h urine collections were obtained. Three (first, second, fourth) were collected in concentrated HCl (0.5 ml) for all measurements except for pH, uric acid, and chloride and two collections (third and fifth) were collected in the presence of thymol for measurement of pH, uric acid, and chloride. All samples were refrigerated at 4°C until measurement and all measurements were completed within 2 weeks.
From days 15 to 28, half of each group (seven GHS and seven Ctl rats), chosen at random, was continued on NCD without modification and the other half (seven GHS and seven Ctl rats) was fed NCD supplemented with Cinacalcet (30 mg/kg/day) (Amgen Inc., Thousand Oaks, CA, USA). This dose has been shown to significantly inhibit PTH in normal rats.36 In humans, the terminal half-life of Cinacalcet is 30–40 h and steady-state drug levels are reached in 7 days.36, 37 During the last 5 days of this period (day 24–28), five successive 24-h urine collections were obtained as during days 10–14.
From days 29 to 42, all GHS and Ctl rats were fed 13 g/day of a LCD (0.02% Ca and 0.65% P). No rat received Cinacalcet. LCD was utilized to remove the contribution of appreciable intestinal Ca absorption to UCa excretion. During the last 5 days of this period (day 38–42), five successive 24-h urine collections were obtained as during days 10–14. From days 43 to 56, half of each group (seven GHS and seven Ctl rats) was continued on LCD without modification and the other half (the same seven GHS and seven Ctl rats that had previously received Cinacalcet) was fed LCD supplemented with Cinacalcet (30 mg/kg/day). During the last 5 days of this period (day 52–56), five successive 24-h urine collections were obtained as during days 10–14.

Absorption, Distribution and Excretion
Rapidly absorbed following oral administration.
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.
1000 L
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. ...
After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half life of 30 to 40 hours. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
Steady-state drug levels are achieved within 7 days. The mean accumulation ratio is approximately 2 with once-daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once-daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma proteins. The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.8 at a blood cinacalcet concentration of 10 ng/mL.
After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. A food-effect study in healthy volunteers indicated that the Cmax and AUC were increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat meal compared with fasting, Cmax and AUC of cinacalcet were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.
For more Absorption, Distribution and Excretion (Complete) data for CINACALCET (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. ... The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.
Cinacalcet is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, mainly CYP3A4, CYP2D6, and CYP1A2, and is a potent inhibitor of CYP2D6 in vitro.
Rapidly and extensively metabolized hepatically by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2 via oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid which are further metabolized via beta-oxidation and glycine conjugations; the oxidative N-dealkylation process also generates metabolites that contains the naphthalene ring; and oxidation of the naphthalene ring on the parent drug to form dihydrodiols which are further conjugated with glucuronic aicd. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 uM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response.

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Biological Half-Life
Terminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.
The mean half life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.
terminal half-life: 30 to 40 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on cinacalcet during breastfeeding. However, several newborn infants with disorders of calcium metabolism have been safely treated with cinacalcet. Cinacalcet levels in milk are unlikely to be as high as the doses used in these case. If cinacalcet is required by the mother, it is not a reason to discontinue breastfeeding. Until more data are available, cinacalcet should only be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Approximately 93 to 97% bound to plasma proteins.

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Interactions
Potential pharmacokinetic interaction (increased plasma concentrations of drugs metabolized principally by cytochrome P450 (CYP) isoenzyme 2D6). In patients receiving cinacalcet 25 or 100 mg concurrently with amitriptyline hydrochloride 50 mg, exposure to amitriptyline and its active metabolite, norrtiptyline, was increased by 20%. Dosage adjustment maybe required if cinacalcet is administered concomitantly with ta drug that has a narrow therapeutic index and is metabolized principally by CYP2D6 (e.g., flecainide, vinblastine, thioridazine, most tricyclic antidepressants).
Potential pharmacokinetic interaction (increased plasma cinacalcet concentrations) with potent CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, itraconazole). Approximate 2.3-fold increase in cinacalcet exposure reported following concomitant administration of a single 90-mg dose of cinacalcet with ketoconazole (200 mg twice daily for 7 days). Cinacalcet dosage adjustment may be required and PTH and serum calcium concentrations should be closely monitored if a potent CYP3A4 inhibitor is initiated or discontinued.

[1]. Kidney Int Suppl . 2003 Jun:(85):S91-6.

[2]. Clin Ther . 2005 Nov;27(11):1725-51.

Cinacalcet hydrochloride is a hydrochloride derived from equimolar amounts of cinacalcet and hydrogen chloride. It has a role as a calcimimetic and a P450 inhibitor. It is functionally related to a cinacalcet.
Cinacalcet Hydrochloride is the orally bioavailable hydrochloride salt of the calcimimetic cinacalcet. Cinacalcet increases the sensitivity of calcium-sensing receptors on chief cells in the parathyroid gland to extracellular calcium, thereby reducing parathyroid hormone (PTH) secretion. A reduction in PTH levels inhibits osteoclast activity, which may result in a decrease in cortical bone turnover and bone fibrosis, and normalization of serum calcium and phosphorus levels. In addition, by reducing PTH levels, cinacalcet may reduce PSA levels; PTH appears to raise PSA levels and may increase prostate cancer cell growth.
See also: Cinacalcet (has active moiety).

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Drug Indication
Secondary hyperparathyroidism AdultsTreatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Paediatric populationTreatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy (see section 4. 4). Cinacalcet Accordpharma may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5. 1). Parathyroid carcinoma and primary hyperparathyroidism in adultsReduction of hypercalcaemia in adult patients with: parathyroid carcinoma. primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Cinacalcet Mylan may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate. Reduction of hypercalcaemia in patients with: parathyroid carcinomaprimary HPT for whom parathyroidectomywould be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.  
Secondary hyperparathyroidism AdultsTreatment of secondary hyperparathyroidism (HPT) in adult patients with end stage renal disease (ESRD) on maintenance dialysis therapy. Paediatric populationTreatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate. Parathyroid carcinoma and primary hyperparathyroidism in adults. Reduction of hypercalcaemia in adult patients with: parathyroid carcinoma; primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.
Treatment of parathyroid carcinoma, Treatment of primary hyperparathyroidism , Treatment of secondary hyperparathyroidism in patients with end-stage renal disease

C22H23CLF3N

393.87

393.147

C, 67.09; H, 5.89; Cl, 9.00; F, 14.47; N, 3.56

364782-34-3

Cinacalcet; 226256-56-0; Cinacalcet-d3 hydrochloride; Cinacalcet-d3

156418

White to off-white solid powder

440.9ºCat760mmHg

175-177ºC

220.5ºC

7.334

12.03

2

4

6

27

422

1

Cl[H].FC(C1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])C([H])([H])C([H])([H])N([H])[C@]([H])(C([H])([H])[H])C1=C([H])C([H])=C([H])C2=C([H])C([H])=C([H])C([H])=C12)(F)F

QANQWUQOEJZMLL-PKLMIRHRSA-N

InChI=1S/C22H22F3N.ClH/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25;/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3;1H/t16-;/m1./s1

N-[(1R)-1-naphthalen-1-ylethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine;hydrochloride

AMG073 HCl; Cinacalcet Hydrochloride; Sensipar; AMG-073 HCl; AMG 073 HCl; KRN1493; KRN-1493; Cinacalcet HCl; Mimpara; Regpara; cinacalcet; cinacalcet hydrochloride; Hydrochloride, Cinacalcet; KRN 1493

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.35 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.35 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.35 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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