Tenapanor (2024)

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Summary

Tenapanor is an NHE3 inhibitor indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic kidney disease,

Brand Names

Ibsrela, Xphozah

Generic Name

Tenapanor

DrugBank Accession Number

DB11761

Background

Tenapanor is a novel, small molecule medication approved in September 2019 for the treatment of constipation-predominant irritable bowel-syndrome (IBS-C).⁶ It was first designed and synthesized in 2012.² As an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) transporter, it is the first and currently only medication within its class^1,2,3 and therefore exists as a novel alternative in the treatment of IBS-C. In October 2023, tenapanor was approved for the treatment of chronic kidney disease.⁷

Type

Small Molecule

Groups

Approved, Investigational

Structure

MOLSDFPDBSMILESInChI

Similar Structures

Structure for Tenapanor (DB11761)

Weight

Average: 1145.04
Monoisotopic: 1142.3097435

Chemical Formula

C₅₀H₆₆Cl₄N₈O₁₀S₂

Synonyms

• Tenapanor

External IDs

• AZD-1722

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Pharmacology

Indication

Tenapanor is indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in adults.⁶

It is also indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.⁷

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Adjunct therapy in treatment of	Chronic kidney disease (ckd)		••••••••••••	•••••	•••••••••• •••••••• •• •• ••••••••••• •• ••••••••• •••••••	••••••
Treatment of	Irritable bowel syndrome with constipation (ibs-c)		••••••••••••	•••••		••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Through the inhibition of dietary sodium absorption tenapanor causes an increase in water secretion into the intestines, thereby decreasing transit time and softening stool consistency.⁶

Mechanism of action

Tenapanor is a locally-acting small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), an antiporter expressed on the apical surface of enterocytes in the small intestine and colon which is involved in sodium-fluid homeostasis. By inhibiting this antiporter tenapanor causes retention of sodium within the lumen of the intestine - this results in an osmotic gradient that draws water into the lumen and softens stool consistency.^6,2,3

There is some evidence that tenapanor can inhibit the uptake of dietary phosphorus in the gastrointestinal tract, though the exact mechanism of this activity has yet to be elucidated.⁵

Target	Actions	Organism
ASodium/hydrogen exchanger 3	inhibitor	Humans

Absorption

Tenapanor undergoes very minimal systemic absorption following oral administration. During clinical trials, plasma concentrations were below the limit of quantitation (i.e. less than 0.5 ng/mL) in the majority of samples from healthy subjects - for this reason, typical pharmaco*kinetic values related to absorption such as AUC and C_max were unable to be ascertained.^6,3

The effects of tenapanor are greatest when administered 5 to 10 minutes before meals.^6,3

Volume of distribution

Not Available

Protein binding

Both tenapanor and its principle metabolite, M1, are highly plasma protein bound at approximately 99% and 97%, respectively. The specific proteins to which tenapanor and its metabolite binds have yet to be elucidated.⁶

Metabolism

The majority of tenapanor's metabolism to its primary metabolite, M1, is catalyzed via CYP3A4/5.⁶ Exposure of tenapanor to hepatic CYP enzymes is likely limited due to its minimal systemic absorption, so its metabolism may be due to intestinal CYP enzyme activity.¹

The M1 metabolite of tenapanor is a P-glycoprotein substrate and, in contrast to its parent drug, can be detected in plasma, reaching a C_max of approximately 15 ng/mL at steady state.⁶ It is not considered active against NHE3.

Hover over products below to view reaction partners

• Tenapanor
  • Tenapanor M1 metabolite

Route of elimination

Following administration of a radio labeled dose of tenapanor, 70% of the radioactivity was excreted in the feces within 120 hours of administration and 79% within 240 hours. Approximately 65% of the total dose is excreted as unchanged parent drug within 144 hours of administration. Only 9% of the administered dose was found in the urine, existing primarily as metabolites. Tenapanor's M1 metabolite is excreted unchanged in the urine and accounts for approximately 1.5% of the total dose within 144 hours of administration.⁶

Half-life

Tenapanor's FDA label states that its half-life could not be determined during clinical trials due to its minimal systemic absorption resulting in plasma concentrations below the limit of quantitation (i.e. less than 0.5 ng/mL).⁶

Clearance

Not Available

Adverse Effects

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Toxicity

Symptoms of overdose are likely to be consistent with tenapanor's adverse effect profile, and may therefore include gastrointestinal effects such as diarrhea. Dehydration may occur depending on duration and severity of diarrhea.⁶ No specific management strategies have been proposed in cases of overdose.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Asunaprevir	The serum concentration of Asunaprevir can be decreased when it is combined with Tenapanor.
Atorvastatin	The serum concentration of Atorvastatin can be decreased when it is combined with Tenapanor.
Fexofenadine	The serum concentration of Fexofenadine can be decreased when it is combined with Tenapanor.
Mesalazine	The serum concentration of Mesalazine can be decreased when it is combined with Tenapanor.

Food Interactions

• Take before a meal. Tenapanor should be administered immediately prior to the first meal of the day and immediately prior to dinner.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tenapanor hydrochloride	50605O2ZNS	1234365-97-9	VFRAXTZDILCRKY-OWRGXFNZSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ibsrela	Tablet	53.2 mg/1	Oral	Ardelyx, Inc.	2019-09-12	Not applicable
Ibsrela	Tablet	50 mg	Oral	Knight Therapeutics Inc.	2020-11-23	Not applicable
XPHOZAH 10 mg	Tablet, film coated	10.6 mg/1	Oral	Ardelyx, Inc.	2023-10-17	Not applicable
XPHOZAH 20 mg	Tablet, film coated	21.3 mg/1	Oral	Ardelyx, Inc.	2023-10-17	Not applicable
XPHOZAH 30 mg	Tablet, film coated	31.9 mg/1	Oral	Ardelyx, Inc.	2023-10-17	Not applicable

Categories

ATC Codes

A06AX08 — Tenapanor

• A06AX — Other drugs for constipation
• A06A — DRUGS FOR CONSTIPATION
• A06 — DRUGS FOR CONSTIPATION
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Alimentary Tract and Metabolism
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Substrates
• Drugs for Constipation
• Heterocyclic Compounds, Fused-Ring
• Organic Anion Transporting Polypeptide 2B1 Inhibitors
• Sodium-Hydrogen Exchanger 3 Inhibitor
• Sodium/Hydrogen Exchanger 3 (NHE3) Inhibitors
• Sulfur Compounds

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 4-phenyltetrahydroisoquinolines. These are compounds containing a phenyl group attached to the C4-atom of a tetrahydroisoquinoline moiety.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Tetrahydroisoquinolines

Sub Class

4-phenyltetrahydroisoquinolines

Direct Parent

4-phenyltetrahydroisoquinolines

Alternative Parents

Benzenesulfonamides / Benzenesulfonyl compounds / Aralkylamines / Organosulfonamides / Aryl chlorides / Aminosulfonyl compounds / Ureas / Trialkylamines / Dialkyl ethers / Azacyclic compounds show 4 more

Substituents

4-phenyltetrahydroisoquinoline / Amine / Aminosulfonyl compound / Aralkylamine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenesulfonamide / Benzenesulfonyl group show 21 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

WYD79216A6

CAS number

1234423-95-0

InChI Key

DNHPDWGIXIMXSA-CXNSMIOJSA-N

InChI

InChI=1S/C50H66Cl4N8O10S2/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)/t43-,44-/m0/s1

IUPAC Name

3-{2-[2-(2-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]benzenesulfonamido}ethoxy)ethoxy]ethyl}-1-{4-[({2-[2-(2-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]benzenesulfonamido}ethoxy)ethoxy]ethyl}carbamoyl)amino]butyl}urea

SMILES

CN1C[C@@H](C2=CC(=CC=C2)S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C2=CC(=CC=C2)[C@@H]2CN(C)CC3=C2C=C(Cl)C=C3Cl)C2=C(C1)C(Cl)=CC(Cl)=C2

References

Synthesis Reference

Jindrich Richter, Ondrej Dammer, Lukas Krejcik, Ludmila Hejtmankova, Petr Lustig, Michal Dousa "Solid forms of tenapanor and method of preparation of tenapanor." WO Patent WO2019091503A1, issued May 2019.

General References

1. 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. [Article]
2. Zielinska 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. [Article]
3. 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. [Article]
4. 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. [Article]
5. Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Dy E, Black D, Zhong Z, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D: Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD. J Am Soc Nephrol. 2015 May;26(5):1138-49. doi: 10.1681/ASN.2014030317. Epub 2014 Nov 17. [Article]
6. FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
7. FDA Approved Drug Products: XPHOZAH (tenapanor) tablets, for oral use [Link]

External Links

PubChem Compound

71587953

PubChem Substance

347828115

ChemSpider

32056950

BindingDB

381823

RxNav

2199674

ChEMBL

CHEMBL3304485

Wikipedia

Tenapanor

Clinical Trials

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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4	Completed	Treatment	Chronic Kidney Disease Requiring Chronic Dialysis / Hyperphosphataemia	1	somestatus	stop reason	just information to hide
4	Completed	Treatment	End Stage Renal Disease (ESRD) / Hyperphosphataemia	1	somestatus	stop reason	just information to hide
4	Not Yet Recruiting	Basic Science	Hyperoxaluria	1	somestatus	stop reason	just information to hide
4	Recruiting	Treatment	Irritable Bowel Syndrome (IBS)	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Hyperphosphataemia	2	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	50 mg
Tablet	Oral	53.2 mg/1
Tablet, film coated	Oral	10.6 mg/1
Tablet, film coated	Oral	21.3 mg/1
Tablet, film coated	Oral	31.9 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9006281	No	2015-04-14	2030-05-02
US9408840	No	2016-08-09	2029-12-30
US8541448	No	2013-09-24	2029-12-30
US8969377	No	2015-03-03	2029-12-30
US10940146	No	2014-04-10	2034-04-10
US10272079	No	2014-04-10	2034-04-10

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Practically insoluble	FDA Label

Predicted Properties

Property	Value	Source
Water Solubility	0.00292 mg/mL	ALOGPS
logP	4.55	ALOGPS
logP	5.02	Chemaxon
logS	-5.6	ALOGPS
pKa (Strongest Acidic)	9.86	Chemaxon
pKa (Strongest Basic)	6.84	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	12	Chemaxon
Hydrogen Donor Count	6	Chemaxon
Polar Surface Area	218 Å2	Chemaxon
Rotatable Bond Count	27	Chemaxon
Refractivity	291.93 m3·mol-1	Chemaxon
Polarizability	120.95 Å3	Chemaxon
Number of Rings	6	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udl-0509017210-bd0c32ab7a1b94266efc
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-0900041100-27d1d7735a34d1385bd8
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-2491002510-97e5f6197cba96791f54
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001i-1102093000-79aeb03fdcd8b975cb83
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-1295102800-cf36a389bd1860eea1d8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0uxr-3317490600-f7c8a0fd7da2a18d9ac8

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	317.89255	predicted	DeepCCS 1.0 (2019)
[M+H]+	319.78796	predicted	DeepCCS 1.0 (2019)
[M+Na]+	325.56592	predicted	DeepCCS 1.0 (2019)

Drug created at October 20, 2016 20:45 / Updated at October 20, 2023 23:04