Tenapanor hydrochloride | AZD-1722 | CAS#1234423-95-0 | 1234365-97-9 | Na+/H+ exchanger 3 (NHE3) inhibitor

MedKoo Cat#: 319720 | Name: Tenapanor HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Tenapanor, also known as AZD-1722 and RDX 5791, 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. Tenapanor possesses an excellent preclinical safety profile and, as of now, there are no serious concerns about its side effects.

Chemical Structure

Tenapanor HCl

CAS#1234365-97-9 (2HCl)

Theoretical Analysis

MedKoo Cat#: 319720

Name: Tenapanor HCl

CAS#: 1234365-97-9 (2HCl)

Chemical Formula: C50H68Cl6N8O10S2

Exact Mass: 1144.3254

Molecular Weight: 1217.96

Elemental Analysis: C, 49.31; H, 5.63; Cl, 17.46; N, 9.20; O, 13.14; S, 5.26

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,750.00	Ready to ship
2g	USD 6,250.00	Ready to ship

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Related CAS #

1234423-95-0 (free base) 1234365-97-9 (2HCl)

Synonym

AZD-1722; AZD 1722; AZD1722; RDX 5791; RDX-5791; RDX5791; Tenapanor; Tenapanor hydrochloride; Tenapanor dihydrochloride; Ibsrela.

IUPAC/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

InChi Key

VFRAXTZDILCRKY-OWRGXFNZSA-N

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

SMILES Code

O=S(C1=CC=CC([C@@H]2CN(C)CC3=C2C=C(Cl)C=C3Cl)=C1)(NCCOCCOCCNC(NCCCCNC(NCCOCCOCCNS(=O)(C4=CC=CC([C@@H]5CN(C)CC6=C5C=C(Cl)C=C6Cl)=C4)=O)=O)=O)=O.[H]Cl.[H]Cl

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO and water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#SSC70407

QC Data

View QC data: current batch, Lot#SSC70407

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Tenapanor is an inhibitor of the Na+/H+ exchanger NHE3 with IC50 values of 5 and 10 nM against human and Rat NHE3, respectively.

In vitro activity:

NHE3 is highly expressed along the length of the gastrointestinal tract and is endogenously expressed in each segment of the intestinal monolayer model, as shown in representative images from the ileum (fig. S1A). Similar to the in vivo situation, most cells in the monolayer are absorptive cells and are polarized, expressing NHE3 only at the apical surface (fig. S1B). Proton secretion coupled to sodium absorption by NHE3 results in acidification of the apical media of the monolayer. This was inhibited by tenapanor, monitored by the color change of pH-sensitive phenol red in the apical media (fig. S1C). Concentration-response studies measuring apical pH using 2’,7’-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM) dye, where a decrease in the fluorescence emission ratio reflects a decrease in pH, showed that tenapanor inhibited apical acid secretion by NHE3 with a half-maximal inhibitory concentration (IC50) of 2 and 6 nM in human and mouse ileum monolayers, respectively (fig. S1D). This is consistent with the potency of tenapanor against NHE3 in primary target assays. In human ileum and duodenum cell monolayer cultures, tenapanor caused a concentration-dependent inhibition of the NHE3-mediated recovery of intracellular pH (pHi) after acid loading (IC50: ileum, 13 nM; duodenum, 9 nM) (fig. S1, E and F). On the basis of the potency of NHE3 inhibition in the intestinal monolayer culture system, subsequent experiments investigating effects on phosphate absorption used a tenapanor concentration of 1 μM to ensure complete NHE3 inhibition. Reference: Sci Transl Med. 2018 Aug 29;10(456):eaam6474. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30158152/

In vivo activity:

Tenapanor reduces phosphate absorption in vivo. In a rat intestinal loop model, tenapanor reduced radioactive phosphate absorption in the jejunum to an amount similar to that observed in sodium-free conditions (Fig. 1A). The jejunum is a key site of intestinal phosphate absorption in rats. Increasing luminal phosphate concentration acutely via oral bolus caused proportionate increases in urinary phosphate excretion, an indirect marker of intestinal phosphate absorption (Fig. 1B). This linear concentration dependence of absorption and failure to saturate, even at high concentrations, is characteristic of passive paracellular absorption. Tenapanor reduced phosphate absorption across all phosphate concentrations, decreasing urinary phosphate excretion even at high phosphate concentrations (Fig. 1B), suggesting that tenapanor reduces paracellular phosphate absorption. Reference: Sci Transl Med. 2018 Aug 29;10(456):eaam6474. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30158152/

	Solvent	mg/mL	mM
Solubility
	DMSO	50.0	43.67

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 1,217.96 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. King AJ, Siegel M, He Y, Nie B, Wang J, Koo-McCoy S, Minassian NA, Jafri Q, Pan D, Kohler J, Kumaraswamy P, Kozuka K, Lewis JG, Dragoli D, Rosenbaum DP, O'Neill D, Plain A, Greasley PJ, Jönsson-Rylander AC, Karlsson D, Behrendt M, Strömstedt M, Ryden-Bergsten T, Knöpfel T, Pastor Arroyo EM, Hernando N, Marks J, Donowitz M, Wagner CA, Alexander RT, Caldwell JS. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018 Aug 29;10(456):eaam6474. doi: 10.1126/scitranslmed.aam6474. PMID: 30158152; PMCID: PMC6454550. 2. Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014 Mar 12;6(227):227ra36. doi: 10.1126/scitranslmed.3007790. PMID: 24622516.

In vivo protocol:

1: Markham A. Tenapanor: First Approval. Drugs. 2019 Nov;79(17):1897-1903. doi: 10.1007/s40265-019-01215-9. Review. PubMed PMID: 31677150. 2: Block GA, Rosenbaum DP, Yan A, Chertow GM. Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial. J Am Soc Nephrol. 2019 Apr;30(4):641-652. doi: 10.1681/ASN.2018080832. Epub 2019 Mar 7. PubMed PMID: 30846557; PubMed Central PMCID: PMC6442342. 3: Kothari S, Vippagunta RR. Predicting the Physical Stability of Amorphous Tenapanor Hydrochloride Using Local Molecular Structure Analysis, Relaxation Time Constants, and Molecular Modeling. Mol Pharm. 2019 Mar 4;16(3):943-951. doi: 10.1021/acs.molpharmaceut.8b00853. Epub 2019 Feb 14. PubMed PMID: 30699296. 4: King AJ, Siegel M, He Y, Nie B, Wang J, Koo-McCoy S, Minassian NA, Jafri Q, Pan D, Kohler J, Kumaraswamy P, Kozuka K, Lewis JG, Dragoli D, Rosenbaum DP, O'Neill D, Plain A, Greasley PJ, Jönsson-Rylander AC, Karlsson D, Behrendt M, Strömstedt M, Ryden-Bergsten T, Knöpfel T, Pastor Arroyo EM, Hernando N, Marks J, Donowitz M, Wagner CA, Alexander RT, Caldwell JS. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018 Aug 29;10(456). pii: eaam6474. doi: 10.1126/scitranslmed.aam6474. PubMed PMID: 30158152; PubMed Central PMCID: PMC6454550. 5: Block GA, Rosenbaum DP, Yan A, Greasley PJ, Chertow GM, Wolf M. The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia. Nephrol Dial Transplant. 2019 Feb 1;34(2):339-346. doi: 10.1093/ndt/gfy061. PubMed PMID: 29617976; PubMed Central PMCID: PMC6365767. 6: Nilsson Lill SO, Widdifield CM, Pettersen A, Svensk Ankarberg A, Lindkvist M, Aldred P, Gracin S, Shankland N, Shankland K, Schantz S, Emsley L. Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-ray Diffraction, NMR Crystallography, and Molecular Modeling. Mol Pharm. 2018 Apr 2;15(4):1476-1487. doi: 10.1021/acs.molpharmaceut.7b01047. Epub 2018 Mar 12. PubMed PMID: 29490140. 7: Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, Safety, and Tolerability of the NHE3 Inhibitor Tenapanor: Two Trials in Healthy Volunteers. Clin Drug Investig. 2018 Apr;38(4):341-351. doi: 10.1007/s40261-017-0614-0. PubMed PMID: 29363027; PubMed Central PMCID: PMC5856883. 8: Visconti L, Cernaro V, Calimeri S, Lacquaniti A, De Gregorio F, Ricciardi CA, Lacava V, Santoro D, Buemi M. The Myth of Water and Salt: From Aquaretics to Tenapanor. J Ren Nutr. 2018 Mar;28(2):73-82. doi: 10.1053/j.jrn.2017.06.005. Epub 2017 Nov 14. Review. PubMed PMID: 29146141. 9: Johansson S, Rosenbaum DP, Palm J, Stefansson B, Knutsson M, Lisbon EA, Hilgendorf C. Tenapanor administration and the activity of the H(+) -coupled transporter PepT1 in healthy volunteers. Br J Clin Pharmacol. 2017 Sep;83(9):2008-2014. doi: 10.1111/bcp.13313. Epub 2017 May 31. PubMed PMID: 28432691; PubMed Central PMCID: PMC5582369. 10: Johansson SA, Knutsson M, Leonsson-Zachrisson M, Rosenbaum DP. Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study. Clin Pharmacol Drug Dev. 2017 Sep;6(5):457-465. doi: 10.1002/cpdd.341. Epub 2017 Mar 24. PubMed PMID: 28339149; PubMed Central PMCID: PMC5599956. 11: Johansson S, Rosenbaum DP, Ahlqvist M, Rollison H, Knutsson M, Stefansson B, Elebring M. Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions. Clin Pharmacol Drug Dev. 2017 Sep;6(5):466-475. doi: 10.1002/cpdd.346. Epub 2017 Mar 16. PubMed PMID: 28301096; PubMed Central PMCID: PMC5599994. 12: Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial. Am J Gastroenterol. 2017 May;112(5):763-774. doi: 10.1038/ajg.2017.41. Epub 2017 Feb 28. PubMed PMID: 28244495; PubMed Central PMCID: PMC5418559. 13: Carney EF. Dialysis: Efficacy of tenapanor in hyperphosphataemia. Nat Rev Nephrol. 2017 Apr;13(4):194. doi: 10.1038/nrneph.2017.27. Epub 2017 Feb 27. PubMed PMID: 28239171. 14: Block GA, Rosenbaum DP, Leonsson-Zachrisson M, Åstrand M, Johansson S, Knutsson M, Langkilde AM, Chertow GM. Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis. J Am Soc Nephrol. 2017 Jun;28(6):1933-1942. doi: 10.1681/ASN.2016080855. Epub 2017 Feb 3. PubMed PMID: 28159782; PubMed Central PMCID: PMC5461797. 15: Johansson S, Leonsson-Zachrisson M, Knutsson M, Spencer AG, Labonté ED, Deshpande D, Kohler J, Kozuka K, Charmot D, Rosenbaum DP. Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders. Clin Pharmacol Drug Dev. 2017 Sep;6(5):448-456. doi: 10.1002/cpdd.307. Epub 2016 Oct 26. PubMed PMID: 27654985; PubMed Central PMCID: PMC5599948. 16: Johansson S, Rosenbaum DP, Knutsson M, Leonsson-Zachrisson M. A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers. Clin Exp Nephrol. 2017 Jun;21(3):407-416. doi: 10.1007/s10157-016-1302-8. Epub 2016 Jul 1. PubMed PMID: 27368672; PubMed Central PMCID: PMC5486465. 17: Block GA, Rosenbaum DP, Leonsson-Zachrisson M, Stefansson BV, Rydén-Bergsten T, Greasley PJ, Johansson SA, Knutsson M, Carlsson BC. Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis. Clin J Am Soc Nephrol. 2016 Sep 7;11(9):1597-605. doi: 10.2215/CJN.09050815. Epub 2016 Jun 23. PubMed PMID: 27340281; PubMed Central PMCID: PMC5012484. 18: Zielińska M, Wasilewski A, Fichna J. Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome. Expert Opin Investig Drugs. 2015;24(8):1093-9. doi: 10.1517/13543784.2015.1054480. Epub 2015 Jun 12. Review. PubMed PMID: 26065434.