Identification

Summary

Tenapanor is an NHE3 inhibitor indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C).

Brand Names
Ibsrela
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 class1,2,3 and therefore exists as a novel alternative in the treatment of IBS-C.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 1145.04
Monoisotopic: 1142.3097435
Chemical Formula
C50H66Cl4N8O10S2
Synonyms
  • Tenapanor
External IDs
  • AZD-1722

Pharmacology

Indication

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

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Associated Conditions
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

TargetActionsOrganism
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 pharmacokinetic values related to absorption such as AUC and Cmax 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 Cmax of approximately 15 ng/mL at steady state.6 It is not considered active against NHE3.

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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.
DrugInteraction
AsunaprevirThe serum concentration of Asunaprevir can be decreased when it is combined with Tenapanor.
AtorvastatinThe serum concentration of Atorvastatin can be decreased when it is combined with Tenapanor.
FexofenadineThe serum concentration of Fexofenadine can be decreased when it is combined with Tenapanor.
PitavastatinThe serum concentration of Pitavastatin can be decreased when it is combined with Tenapanor.
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Food Interactions
  • Take before a meal. Tenapanor should be administered immediately prior to the first meal of the day and immediately prior to dinner.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Tenapanor hydrochloride50605O2ZNS1234365-97-9VFRAXTZDILCRKY-OWRGXFNZSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IbsrelaTablet50 mgOralKnight Therapeutics Inc.2020-11-23Not applicableCanada flag
IbsrelaTablet53.2 mg/1OralArdelyx, Inc.2019-09-12Not applicableUS flag

Categories

ATC Codes
A06AX08 — Tenapanor
Drug Categories
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]
PubChem Compound
71587953
PubChem Substance
347828115
ChemSpider
32056950
BindingDB
381823
RxNav
2199674
ChEMBL
CHEMBL3304485
Wikipedia
Tenapanor

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentChronic Kidney Disease Requiring Chronic Dialysis / Hyperphosphataemia1
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hyperphosphataemia1
3CompletedTreatmentConstipation-predominant Irritable Bowel Syndrome (IBS-C)3
3CompletedTreatmentHyperphosphataemia2
2CompletedTreatmentChronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus1
2CompletedTreatmentEnd Stage Renal Disease (ESRD) / Stage 5 Chronic Kidney Disease (CKD)1
2CompletedTreatmentHyperphosphataemia2
2, 3CompletedTreatmentConstipation-predominant Irritable Bowel Syndrome (IBS-C)1
2, 3CompletedTreatmentHyperphosphataemia1
1CompletedBasic ScienceHealthy Subjects (HS)5

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral50 mg
TabletOral53.2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9006281No2015-04-142030-05-02US flag
US9408840No2016-08-092029-12-30US flag
US8541448No2013-09-242029-12-30US flag
US8969377No2015-03-032029-12-30US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00292 mg/mLALOGPS
logP4.55ALOGPS
logP5.02ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)9.86ChemAxon
pKa (Strongest Basic)6.84ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area218 Å2ChemAxon
Rotatable Bond Count27ChemAxon
Refractivity291.93 m3·mol-1ChemAxon
Polarizability120.95 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient (PubMed:26358773). Plays an important role in signal transduction.
Specific Function
Pdz domain binding
Gene Name
SLC9A3
Uniprot ID
P48764
Uniprot Name
Sodium/hydrogen exchanger 3
Molecular Weight
92853.665 Da
References
  1. FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. FDA Approved Drug Products: Isbrela (tenapanor) tablets for oral use [Link]

Drug created at October 20, 2016 20:45 / Updated at April 23, 2022 03:43