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| Targets |
Evocalcet selectively targets the calcium-sensing receptor (CaSR) on parathyroid cells. As an allosteric agonist, evocalcet binds to CaSR via allosteric action and activates the receptor. Activation of CaSR suppresses parathyroid hormone (PTH) secretion from parathyroid gland cells, regulating blood calcium levels. This prevents PTH-mediated calcium outflow from bones and restores calcium levels to normal. Evocalcet has an EC₅₀ of 92.7 nM for human CaSR.
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| ln Vitro |
In hCaR-HEK293 cells, evocalcet (0, 20 and 60 nM) significantly elevated [Ca2+]i, with a median EC50 value of 92.7 nM [2]. Cytochrome P450 (CYP) isoenzyme cardiovascular activity is not significantly inhibited by evocalcet [2].
In vitro, evocalcet induces intracellular calcium release in HEK293 cells expressing human CaSR with an EC₅₀ of 92.7 nM. In hCaR-HEK293 cells, evocalcet (0, 20, and 60 nM) dose-dependently increases cytosolic [Ca²⁺] concentration. The compound shows high selectivity for CaSR over other receptors, contributing to its targeted mechanism of action. Evocalcet's activity is characterized by its ability to activate CaSR and suppress PTH secretion. |
| ln Vivo |
The effects of evocalcet (0.03 or 0.3 mg/kg; epidermis, once) on calcium and serum parathyroid hormone are reported [1]. For five weeks, Evocalcet (0.3 mg/kg; side, once daily) lowers serum parathyroid hormone.
In vivo, evocalcet effectively suppresses serum parathyroid hormone (PTH) production in animal models and clinical studies. The compound reduces serum calcium and phosphorus levels, helping to manage SHPT in patients with chronic kidney disease. As an orally active agent, evocalcet offers convenient once-daily dosing for long-term management of hyperparathyroidism. Clinical studies have demonstrated efficacy in reducing PTH levels with a favorable safety profile. |
| Enzyme Assay |
Non-cellular receptor binding assays for evocalcet involve competitive radioligand binding displacement studies using membrane preparations from cells expressing the human calcium-sensing receptor. Membranes are incubated with a radiolabeled CaSR ligand and varying concentrations of evocalcet. Following incubation and filtration, bound radioactivity is measured by scintillation counting. IC₅₀ values are determined from displacement curves and converted to Ki values. Allosteric modulation can be assessed using calcium mobilization assays in cell-free membrane preparations.
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| Cell Assay |
In vitro cellular assays for evocalcet involve treating HEK293 cells expressing human CaSR with the compound and measuring intracellular calcium release. Cells are loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4) and treated with varying concentrations of evocalcet (0-100 nM). The increase in intracellular calcium concentration is measured using a fluorescence plate reader. EC₅₀ values for CaSR activation are determined from dose-response curves. PTH suppression can be assessed in parathyroid cell cultures.
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| Animal Protocol |
Animal/Disease Models: Male Sprague Dawley chronic kidney disease (SHPT) with adenine-induced secondary hyperparathyroidism (SHPT) CKD) rats [1]
Doses: 0.03 and 0.3 mg/kg Route of Administration: oral administration and calcium levels, increase inorganic phosphorus in serum [1]. ; 0.03 and 0.3 mg/kg, primary Experimental Results: The 0.3 mg/kg dose diminished serum PTH and Ca levels. In vivo animal experiments with evocalcet are conducted in rodent models of chronic kidney disease and secondary hyperparathyroidism. Rats with induced renal failure are treated with evocalcet via oral gavage at various doses. Serum PTH, calcium, and phosphorus levels are measured at multiple time points post-administration. Parathyroid gland histology and bone turnover markers are assessed to evaluate the compound's effects on the PTH-calcium axis and bone metabolism. |
| ADME/Pharmacokinetics |
Evocalcet has a molecular weight of 374.48 and a molecular formula of C₂₄H₂₆N₂O₂. It is a solid at room temperature with a purity of ≥98%. The compound is soluble in DMSO and other organic solvents. It is typically stored at -20°C, protected from light and moisture. Evocalcet is orally bioavailable with favorable pharmacokinetic properties, including a half-life suitable for once-daily dosing in clinical use.
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| Toxicity/Toxicokinetics |
Evocalcet is generally well-tolerated at therapeutic doses. Common side effects include gastrointestinal disturbances such as nausea and vomiting, which are dose-dependent. As a calcimimetic agent, evocalcet may cause hypocalcemia if doses are not properly adjusted. The compound should be used with caution in patients with low baseline calcium levels. Regular monitoring of serum calcium and PTH is recommended during treatment.
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| References |
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| Additional Infomation |
Evocalcet has been used in trials for the treatment of hyperparathyroidism and secondary hyperparathyroidism. Evocalcet is an oral calcium receptor (CaR) modulator with potential calcimimetic activity. After administration, Evocalcet binds to CaR via allosteric action and inhibits its activity, thereby suppressing serum parathyroid hormone (PTH) production, preventing PTH-mediated calcium outflow from bones, and restoring calcium levels to normal.
Evocalcet (KHK7580; CAS 870964-67-3) is a next-generation, orally active calcium-sensing receptor agonist with an EC₅₀ of 92.7 nM for human CaSR. It is approved in Japan for the treatment of secondary hyperparathyroidism in chronic kidney disease patients under the brand name Orkedia. Evocalcet offers advantages over first-generation calcimimetics, including a more favorable side effect profile and convenient once-daily dosing. |
| Molecular Formula |
C24H26N2O2
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|---|---|
| Molecular Weight |
374.48
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| Exact Mass |
374.199
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| CAS # |
870964-67-3
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| PubChem CID |
71242808
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
594.4±50.0 °C at 760 mmHg
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| Flash Point |
313.3±30.1 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.666
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| LogP |
4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
517
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H](C1=CC=CC2=CC=CC=C21)N[C@H]3CCN(C3)C4=CC=C(C=C4)CC(=O)O
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| InChi Key |
RZNUIYPHQFXBAN-XLIONFOSSA-N
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| InChi Code |
InChI=1S/C24H26N2O2/c1-17(22-8-4-6-19-5-2-3-7-23(19)22)25-20-13-14-26(16-20)21-11-9-18(10-12-21)15-24(27)28/h2-12,17,20,25H,13-16H2,1H3,(H,27,28)/t17-,20+/m1/s1
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| Chemical Name |
2-[4-[(3S)-3-[[(1R)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]acetic acid
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| Synonyms |
MT4580; MT 4580; MT-4580
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~30 mg/mL (~80.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.68 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 (6.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6704 mL | 13.3518 mL | 26.7037 mL | |
| 5 mM | 0.5341 mL | 2.6704 mL | 5.3407 mL | |
| 10 mM | 0.2670 mL | 1.3352 mL | 2.6704 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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