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NPS-2143 (also called SB262470; NPS-2143; SB-262470; NPS 2143; SB-262470A) is a potent and selective antagonist of calcium-sensing receptor (CaSR) with the potential to be used for the treatment of osteoporosis. It has an IC50 of 43 nM for CaSR inhibition.
Physicochemical Properties
| Molecular Formula | C24H25CLN2O2 | |
| Molecular Weight | 408.92 | |
| Exact Mass | 408.16 | |
| Elemental Analysis | C, 70.49; H, 6.16; Cl, 8.67; N, 6.85; O, 7.82 | |
| CAS # | 284035-33-2 | |
| Related CAS # | NPS-2143 hydrochloride; 324523-20-8 | |
| PubChem CID | 6918446 | |
| Appearance | White to off-white solid powder | |
| Density | 1.23 g/cm3 | |
| Boiling Point | 608.4ºC at 760 mmHg | |
| Vapour Pressure | 1.17E-15mmHg at 25°C | |
| Index of Refraction | 1.631 | |
| LogP | 5.106 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 8 | |
| Heavy Atom Count | 29 | |
| Complexity | 560 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | N#CC1=C(OC[C@@H](CNC(C)(CC2=CC=C3C=CC=CC3=C2)C)O)C=CC=C1Cl |
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| InChi Key | PZUJQWHTIRWCID-HXUWFJFHSA-N | |
| InChi Code | InChI=1S/C24H25ClN2O2/c1-24(2,13-17-10-11-18-6-3-4-7-19(18)12-17)27-15-20(28)16-29-23-9-5-8-22(25)21(23)14-26/h3-12,20,27-28H,13,15-16H2,1-2H3/t20-/m1/s1 | |
| Chemical Name | 2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Ca2125 receptor ( IC50 = 43 nM ) | |
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| Enzyme Assay | The HEK 293 4.0-7 clonal cell line is utilized in a high-throughput screening format to identify Ca2+2+ receptor agonists and allosteric activators. A quantitative and functional evaluation of the Ca2+2+ receptor activity in these cells Ca2+n be obtained by measuring changes in the concentration of cytoplasmic [Ca2+2+]i. The outcomes of this assay are comparable to those obtained using a homologous expression system of bovine parathyroid cells. Using a fluorescence imaging plate reader or a specially designed spectrofluorimeter, HEK 293 4.0-7 cells loaded with either fura-2 or fluo-3 Ca2+n have their fluorescence measured continuously and online. The concentration of extracellular Ca2+2+ is increased from 1.0 mM to 1.75 mM after NPS-2143 has been incubated with cells for one minute. Individual NPS-2143 tests are conducted at concentrations ranging from 20 μM to 80 μM, with those that inhibit the control response by more than 40% deemed biologiCa2+lly active. Concentration-response curves are used to ascertain the potencies (IC50) of NPS-2143 with biologiCa2+l activity. Following this, an initial evaluation of selectivity is conducted by examining the effects of NPS-2143 at a concentration several times that of its IC50 on [Ca2+2+]i evoked by other G protein-coupled receptors. The activation of intracellular Ca2+2+ is correlated with the expression of thrombin, bradykinin, and ATP receptors in wild-type HEK 293 cells as well as HEK 293 4.0-7 cells. To evaluate a compound's nonselective action on G protein-coupled receptors quickly, these responses Ca2+n be examined. Other assays for selectivity involve using HEK 293 cells that have been modified to express receptors that are most similar to the Ca2+2+ receptor in terms of topology and sequence. These comprise GABABRs (gamma-aminobutyric acid type B) and various metabotropic glutamate receptors, either native or chimeric. In order to couple to the activation of phospholipase C and the release of intracellular Ca2+2+ in HEK 293 cells, chimeric receptors are synthesized using partial sequences of metabotropic glutamate receptors and Ca2+2+ receptors. In an iterative process, NPS-2143 lacking pan-activity are then exposed to structural modifiCa2+tions, and their potencies and selectivities are tracked using these HEK 293 4.0-7 cell assays. | |
| Cell Assay | Calcilytics NPS-2143 has been shown to reduce the CaSR's sensitivity to [Ca2+]o, which attenuates signal transduction in vitro and increases PTH secretion in vivo. Furthermore, for the wild-type CaSR and mutant CaSR (T151R, P221L, E767Q, G830S, and A844T), respectively, the EC50 values of NPS-2143 are 4.27, 1.56, 1.61, 2.46, 2.07, and 3.15 mM. In addition to this, it has been shown that NPS-2143 inhibits the [Ca2+]o-induced cytosolic calcium signal in HEK 293T cells expressing CaSR in a concentration-dependent way. | |
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| References |
[1]. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther. 2001 Oct;299(1):323-31. [2]. Hypertensive effect of calcilytic NPS 2143 administration in rats. J Endocrinol. 2006 Oct;191(1):189-95. [3]. Involvement of the calcium-sensing receptor in human taste perception. J Biol Chem. 2010 Jan 8;285(2):1016-22. [4]. Calcium-sensing receptor mediates dietary peptide-induced CCK secretion in enteroendocrine STC-1 cells. Mol Nutr Food Res. 2012 May;56(5):753-60. [5]. Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1309-17. |
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| Additional Infomation |
Drug Indication Investigated for use/treatment in osteoporosis. Mechanism of Action NPS-2143 is the prototype calcilytic drug, designed to act on calcium receptors on the surface of parathyroid glands, stimulating the release of the body's own stores of native parathyroid hormone (PTH). |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 2% DMSO +Corn oil : 10mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4455 mL | 12.2273 mL | 24.4547 mL | |
| 5 mM | 0.4891 mL | 2.4455 mL | 4.8909 mL | |
| 10 mM | 0.2445 mL | 1.2227 mL | 2.4455 mL |