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Purity: ≥98%
Tenapanor 2HCl (formerly AZD-1722; AZD1722; RDX-5791; RDX 5791; Ibsrela), the dihydrochloride salt of Tenapanor, is a novel and potent inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3 approved in 2019 for the treatment of irritable bowel syndrome with constipation (IBS-C). It inhibits intestinal sodium/hydrogen exchanger 3 (NHE3) with IC50 values of 5 and 10 nM against human and Rat NHE3, respectively. Na+/H+ exchanger NHE3 plays a prominent role in sodium handling in the gastrointestinal tract and kidney. Tenapanor possesses an excellent preclinical safety profile and there are no serious side effects reported so far. The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.
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| ln Vitro |
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| ln Vivo |
In rats, tenapanor hydrochloride (0.15, 0.5 mg/kg; po) decreases the absorption of phosphate from passive paracellular sources[1]. Rats given tenapanor hydrochloride (0.15 mg/kg; po; twice daily for 11 days in a row) have a greater decrease in the excretion of phosphorus in their urine [2].
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| Cell Assay |
Tenapanor inhibits paracellular phosphate flux in an intestinal epithelial cellular model
Intestinal epithelial stem cells from human or mouse gastrointestinal biopsies cultured as monolayers allow for monitoring of ion transport across the intestinal epithelium. The enteroid monolayer contains the diversity of intestinal epithelial cell lineages, models the specific gene expression patterns of each individual intestinal segment, expresses the appropriate endogenous ion transporters (for example, NHE3 and NaPi2b) in a segment-specific manner, polarizes to form tight junctions with segment-specific expression of claudins and other tight junction proteins, and generates the expected negative luminal electrical potential observed in vivo. The differentiated enteroid monolayer therefore enables the study of transcellular and paracellular phosphate absorption[1].
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| Animal Protocol |
Animal/Disease Models: Rats (intestinal loop model)[1]
Doses: 0.15, 0.5 mg/kg Route of Administration: Po Experimental Results: decreased passive paracellular phosphate absorption by decreased urinary phosphate and sodium excretion after the high-phosphate meal and increased sodium and phosphate delivery to the cecum. Animal/Disease Models: 8 weeks, 250 g male Sprague–Dawley rats[2] Doses: 0.15 mg/kg in combination with sevelamer (0%, 0.75%, 1.5%, and 3% (wt/wt )) Route of Administration: po (oral gavage); twice-daily for 11 days Experimental Results: Dramatically augmented the reduction in urinary phosphorus excretion. |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Tenapanor is essentially non-absorbed systemically, with undetectable plasma concentrations following oral administration. The minimal systemic absorption of tenapanor will not result in a clinically relevant exposure to breastfed infants. No special precautions are necessary. ◉ 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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| References |
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| Additional Infomation |
See also: Tenapanor (has active moiety).
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| Molecular Formula |
C50H68CL6N8O10S2
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| Molecular Weight |
1217.9705247879
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| Exact Mass |
1214.263
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| Elemental Analysis |
C, 49.31; H, 5.63; Cl, 17.46; N, 9.20; O, 13.14; S, 5.26
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| CAS # |
1234365-97-9
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| Related CAS # |
Tenapanor;1234423-95-0
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| PubChem CID |
78131177
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
29
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| Heavy Atom Count |
76
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| Complexity |
1770
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1=CC(=CC2=C1CN(C)C[C@H]2C1C=CC=C(C=1)S(NCCOCCOCCNC(NCCCCNC(NCCOCCOCCNS(C1=CC=CC(=C1)[C@H]1C2C=C(C=C(C=2CN(C)C1)Cl)Cl)(=O)=O)=O)=O)(=O)=O)Cl.Cl.Cl
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| InChi Key |
VFRAXTZDILCRKY-OWRGXFNZSA-N
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| InChi Code |
InChI=1S/C50H66Cl4N8O10S2.2ClH/c1-61-31-43(41-27-37(51)29-47(53)45(41)33-61)35-7-5-9-39(25-35)73(65,66)59-15-19-71-23-21-69-17-13-57-49(63)55-11-3-4-12-56-50(64)58-14-18-70-22-24-72-20-16-60-74(67,68)40-10-6-8-36(26-40)44-32-62(2)34-46-42(44)28-38(52)30-48(46)54;;/h5-10,25-30,43-44,59-60H,3-4,11-24,31-34H2,1-2H3,(H2,55,57,63)(H2,56,58,64);2*1H/t43-,44-;;/m0../s1
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| Chemical Name |
3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)benzenesulfonamide dihydrochloride
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| Synonyms |
RDX 5791; AZD 1722; RDX-5791; AZD-1722; RDX5791; AZD1722; Ibsrela; Tenapanor hydrochloride; Tenapanor dihydrochloride
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
H2O : ~20 mg/mL (~16.42 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8210 mL | 4.1052 mL | 8.2104 mL | |
| 5 mM | 0.1642 mL | 0.8210 mL | 1.6421 mL | |
| 10 mM | 0.0821 mL | 0.4105 mL | 0.8210 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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