NPS-2143
(Synonyms: 2-氯-6-[(2R)-3-[[1,1-二甲基-2-(2-萘基)乙基]氨基]-2-羟基丙氧基]苯腈,SB-262470A) 目录号 : GC16943
An orally-active CaSR antagonist
Cas No.:284035-33-2
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.00%
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- Datasheet
| Cell experiment [1]: | |
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Cell lines |
breast cancer cell line (MDA-MB-231 and MCF-7 ) |
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Preparation Method |
The biological effects of various concentrations of NPS-2143 on breast cancer cell proliferation measured by in vitro MTT assay. |
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Reaction Conditions |
0.5-10 µM NPS-2143 for 48 h. |
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Applications |
The cell viability of both MDA-MB-231 and MCF-7 cells was reduced after NPS-2143 treatment in a dose-dependent manner. 5-10 µM NPS-2143 significantly reduced MCF-7 and MDA-MB-23 cell viability as compared to DMSO-treated controls. |
| Animal experiment [2]: | |
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Animal models |
wild-type, Nuf/+, and Nuf/Nuf mice |
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Preparation Method |
A single bolus of NPS 2143 or vehicle (15% aqueous solution of 2-hydroxypropyl- β-cyclodextrin) was administered to mice. Plasma samples were obtained at either 0, 1, 4, or 24 hours by tail vein or terminal bleed. |
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Dosage form |
30 mg/kg, i.p. injection |
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Applications |
NPS-2143 successfully improved the hypocalcemia associated with Nuf/+ and Nuf/Nuf mice compared with mice given the drug vehicle alone or untreated mice. At 4 hours after NPS 2143 administration, plasma calcium values remained significantly elevated in wild-type and affected Nuf/+ mice compared with respective untreated mice. |
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References: [1]. Alqudah MAY, Azaizeh M, et al. Calcium-Sensing Receptor Antagonist NPS-2143 Inhibits Breast Cancer cell Proliferation, Migration and Invasion via Downregulation of p-ERK1/2, Bcl-2 and Integrin β1 and Induces Caspase 3/7 Activation. Adv Pharm Bull. 2022 Mar;12(2):383-388. [2]. Hannan FM, Walls GV, et al. The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology. 2015 Sep;156(9):3114-21. |
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NPS-2143 is a calcification drug that acts as an antagonist of the calcium-sensing receptor (CaSR) and consequently stimulates the release of parathyroid hormone[1].
Treating Cortical nontumorigenic adult human astrocytes(NAHAs) with fAβ25–35 alone significantly increased at 48 h the release of cytokines and chemokines into the conditioned media. However, NPS-2143(100nM) effectively hinders the Secretion of cytokines and chemokines: IL-6, MCP-2, RANTES, and s-ICAM-1 from NAHAs[2].
NPS-2143 significantly reduced cell proliferation with halfmaximal (50%) inhibitory concentration (IC50) values of 4.08 and 5.71 μM in MDA-MB-231 and MCF-7 cells, respectively. NPS-2143 induced caspase 3/7 activation in MDA-MB-231 breastcancer cells which was accompanied with a remarkable reduction in the expression of Bcl-2antiapoptotic protein. NPS-2143 suppressed migratory and invasive abilities of MDA-MB-231cells with a significant reduction in the expression of p-ERK1/2 and integrin β1 proteins.NPS-2143 to suppress proliferative, migratory andinvasive effects of breast cancer cells which was accompanied by caspase 3/7 activation andsuggests the potential of NPS-2143 as a promising anti-cancer molecule in breast cancer[3].
NPS-2143 was administered as a single ip bolus to wild-type and?Nuf?mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS-2143 rectifying the gain-of-function associated with the?Nuf?mouse CaSR mutation. Intraperitoneal injection of NPS-2143 in?Nuf?mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS-2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder[4].
References:
[1].Wang S, Qiu L, et al. NPS - 2143 (hydrochloride) inhibits melanoma cancer cell proliferation and induces autophagy and apoptosis. Med Sci (Paris). 2018 Oct;34 Focus issue F1:87-93.?
[2].Chiarini A, Armato U, et al. CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes. Cells. 2020 Jun 2;9(6):1386.
[3].Alqudah MAY, Azaizeh M, et al. Calcium-Sensing Receptor Antagonist NPS-2143 Inhibits Breast Cancer cell Proliferation, Migration and Invasion via Downregulation of p-ERK1/2, Bcl-2 and Integrin β1 and Induces Caspase 3/7 Activation. Adv Pharm Bull. 2022 Mar;12(2):383-388.
[4].Hannan FM, Walls GV, et al. The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology. 2015 Sep;156(9):3114-21.
NPS-2143 是一种钙化药物，可作为钙敏感受体 (CaSR) 的拮抗剂，从而刺激甲状旁腺激素的释放[1]。
单独使用 fAβ25-35 处理皮层非致瘤性成人星形胶质细胞 (NAHA)，在 48 小时后，细胞因子和趋化因子释放到条件培养基中会显着增加。然而，NPS-2143(100nM) 可有效抑制细胞因子和趋化因子的分泌:IL-6、MCP-2、RANTES 和 s-ICAM-1 来自 NAHAs[2]。
NPS-2143 在 MDA-MB-231 和 MCF-7 细胞中显着降低细胞增殖，半数最大 (50%) 抑制浓度 (IC50) 值分别为 4.08 和 5.71 μM。 NPS-2143 在 MDA-MB-231 乳腺癌细胞中诱导 caspase 3/7 激活，同时 Bcl-2 抗凋亡蛋白的表达显着降低。 NPS-2143 抑制 MDA-MB-231 细胞的迁移和侵袭能力，显着降低 p-ERK1/2 和整合素 β1 蛋白的表达。NPS-2143 抑制乳腺癌细胞的增殖、迁移和侵袭作用，并伴有caspase 3/7 激活表明 NPS-2143 具有作为乳腺癌抗癌分子的潜力[3]。
NPS-2143 作为单次腹腔推注给药于野生型和 Nuf 小鼠，并测量钙和 PTH 的血浆浓度，并测量尿钙排泄。 NPS-2143 的体外给药纠正了与 Nuf 小鼠 CaSR 突变相关的功能获得。在 Nuf 小鼠中腹膜内注射 NPS-2143 可导致血浆钙和 PTH 显着增加，而不会增加尿钙排泄。这些对具有激活 CaSR 突变的小鼠模型的研究表明，NPS-2143 可使引起 ADH1 的功能获得正常化并改善与该疾病相关的低钙血症[4]。
| Cas No. | 284035-33-2 | SDF | |
| 别名 | 2-氯-6-[(2R)-3-[[1,1-二甲基-2-(2-萘基)乙基]氨基]-2-羟基丙氧基]苯腈,SB-262470A | ||
| 化学名 | 2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile | ||
| Canonical SMILES | CC(C)(CC1=CC2=CC=CC=C2C=C1)NCC(COC3=C(C(=CC=C3)Cl)C#N)O | ||
| 分子式 | C24H25ClN2O2 | 分子量 | 408.93 |
| 溶解度 | ≥ 40.9mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4454 mL | 12.227 mL | 24.4541 mL |
| 5 mM | 0.4891 mL | 2.4454 mL | 4.8908 mL |
| 10 mM | 0.2445 mL | 1.2227 mL | 2.4454 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
NPS 2143, a selective calcium-sensing receptor antagonist inhibits lipopolysaccharide-induced pulmonary inflammation
NPS 2143, a novel and selective antagonist of calcium-sensing receptor (CaSR) has been reported to possess anti-inflammatory activity. In the present study, we examined the protective effect of NPS 2143 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). NPS 2143 pretreatment significantly inhibited the influx of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung of mice with LPS-induced ALI. NPS 2143 decreased the levels of neutrophil elastase (NE) and protein concentration in the bronchoalveolar lavage fluid (BALF). NPS 2143 also reduced the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF and serum. In addition, NPS 2143 attenuated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased the activation of AMP-activated protein kinase (AMPK) in the lung. NPS 2143 also downregulated the activation of nuclear factor-kappa B (NF-κB) in the lung. In LPS-stimulated H292 airway epithelial cells, NPS 2143 attenuated the releases of IL-6 and MCP-1. Furthermore, NPS 2143 upregulated the activation of AMPK and downregulated the activation of NF-κB. These results suggest that NPS 2143 could be potential agent for the treatment of inflammatory diseases including ALI.
Calcium-Sensing Receptor Antagonist NPS-2143 Inhibits Breast Cancer cell Proliferation, Migration and Invasion via Downregulation of p-ERK1/2, Bcl-2 and Integrin β1 and Induces Caspase 3/7 Activation
Purpose: Calcium-sensing receptor (CaSR) has been associated with breast cancer metastasis tothe bone. Targeting chemoattractant factors, such as calcium, that are released in response tobone resorption could prevent metastasis and induce apoptosis of cancer cells. In the presentstudy, we investigated the potential caspase 3/7 activation following treatment with a CaSRantagonist, NPS-2143, in breast cancer cells. In addition, the effects of NPS-2143 on breastcancer cell proliferation, migration and invasion were assessed. Methods: Colorimetric MTT assay was used to evaluate cell viability. Apo-one homogeneouscaspase-3/7 assay was used to measure caspase 3/7 activities in breast cancer cells. Cellmigration and invasion were assessed using scratch wound assay and matrigel invasionchambers, respectively. The protein expressions of p-ERK1/2, integrin β1 and Bcl-2 wereevaluated using western blotting. Results: Our study revealed that NPS-2143 significantly reduced cell proliferation with halfmaximal (50%) inhibitory concentration (IC50) values of 4.08 and 5.71 μM in MDA-MB-231 and MCF-7 cells, respectively. NPS-2143 induced caspase 3/7 activation in MDA-MB-231 breastcancer cells which was accompanied with a remarkable reduction in the expression of Bcl-2antiapoptotic protein. NPS-2143 suppressed migratory and invasive abilities of MDA-MB-231cells with a significant reduction in the expression of p-ERK1/2 and integrin β1 proteins. Conclusion: Our study confirms the ability NPS-2143 to suppress proliferative, migratory andinvasive effects of breast cancer cells which was accompanied by caspase 3/7 activation andsuggests the potential of NPS-2143 as a promising anti-cancer molecule in breast cancer.
Calcium-sensing receptor antagonist NPS-2143 suppresses proliferation and invasion of gastric cancer cells
NPS-2143 is a calcium-sensing receptor (CaSR) antagonist that has been demonstrated to possess anticancer activity. To date, the effects of NPS-2143 on gastric cancer (GC) cell growth, motility, and apoptosis have not been investigated. In the present study, we firstly investigated the expression of CaSR in GC tissues using immunohistochemistry and western blotting. Then Cell Counting Kit-8 and colony formation assays were conducted to explore the effect of the NPS-2143 on the proliferation of GC cell line AGS. Transwell invasion and migration assays were performed to test the effect of NPS-2143 on AGS cell motility. We determined the percentage of apoptotic cells by flow cytometry and explored the changes of apoptosis-related protein by western blotting. Furthermore, we constructed a CaSR knockdown AGS cell line to determine whether NPS-2143 acted via inhibition of CaSR. We found that the protein expression level of CaSR was higher in GC tissues compared with the paired adjacent normal tissues. In addition, NPS-2143 treatment caused an inhibitory effect on the proliferation, invasion, and migration of AGS cells and a promoting effect on AGS apoptosis. The expression of Bcl-2 was decreased while the levels of Bax and active caspase 3 were enhanced in AGS cells after NPS-2143 treatment. Mechanistically, NPS-2143 lead to a significant decrease in the expression of phosphorylated (p)-AKT, phosphorylated mechanistic target of rapamycin (p-mTOR), p70, and cyclin D1. Knockdown of CaSR also suppressed cell proliferation, invasion, and migration and promoted cell apoptosis. No significant difference was observed between CaSR-silenced AGS cells with and without NPS-2143 treatment. These results confirmed that NPS-2143 has an inhibitory influence on AGS cell growth via inhibiting CaSR, which then suppresses the PI3K/Akt signaling pathway.
NPS - 2143 (hydrochloride) inhibits melanoma cancer cell proliferation and induces autophagy and apoptosis
Melanoma is a common and aggressive skin cancer caused by the oncogenic transformation of melanocytes. NPS-2143 (hydrochloride) is a calcification drug that acts as an antagonist of the calcium-sensing receptor (CaSR) and consequently stimulates the release of parathyroid hormone. In the present work, we treated cells from the human melanoma cell line M14 to investigate the effects of NPS-2143 on melanoma cells and elucidate their underlying mechanisms. We observed that NPS-2143 inhibits the survival and proliferation of M14 cells and suppresses the migration and proliferation of M14 cells by inducing apoptosis. The Bax/Bcl?2 ratio in M14 cells was enhanced by the NPS-2143 treatment, suggesting that the mitochondrial apoptotic pathway was activated. The expression and phosphorylation of proteins involved in the PI3K signaling pathway were altered by NPS-2143 treatment. Our data show that NPS-2143 impacts the viability and induces the apoptosis of melanoma M14 cells through its impact on the PI3K signaling pathway. It suggests that NPS-2143 could represent a promising candidate for melanoma treatment.
Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons
Despite numerous efforts and studies over the last three decades, Alzheimer's disease (AD) remains a disorder not fully understood and incurable so far. Development of induced pluripotent stem cell (iPSC) technology to obtain terminally differentiated neurons from adult somatic cells revolutionized the study of AD, providing a powerful tool for modelling the disease and for screening candidate drugs. Indeed, iPSC reprogramming allowed generation of neurons from both sporadic and familial AD patients with the promise to recapitulate the early pathological mechanisms in vitro and to identify novel targets. Interestingly, NPS 2143, a negative allosteric modulator of the calcium sensing receptor, has been indicated as a possible therapeutic for AD. In the present study, we assessed the potential of our iPSC-based familial AD cellular model as a platform for drug testing. We found that iPSC-derived neurons respond to treatment with γ-secretase inhibitor, modifying the physiological amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) secretion. Moreover, we demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Finally, we showed that calcilytic NPS 2143 induced a changing of Aβ and sAβPPα secreted into conditioned media and modulation of CaSR and PSEN1 expression at the plasma membrane of AD neurons. Overall, our findings suggest that NPS 2143 affects important AD processes in a relevant in vitro system of familial AD.