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.

Structure

Similar Structures

Synonyms

Tenapanor

External IDs

AZD-1722

Product Ingredients

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

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Ibsrela	Tablet	53.2 mg/1	Oral	Ardelyx, Inc.	2019-09-12	Not applicable

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

Learn more

Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

Learn more

Categories

UNII

WYD79216A6

CAS number

1234423-95-0

Weight

Average: 1145.04
Monoisotopic: 1142.3097435

Chemical Formula

C₅₀H₆₆Cl₄N₈O₁₀S₂

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

Pharmacology

Indication

Tenapanor is indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in adults.⁶ It is also currently being investigated as a treatment for hyperphosphatemia in chronic kidney disease patients undergoing dialysis (NCT02081534 and NCT02675998).¹

Associated Conditions

Constipation-predominant Irritable Bowel Syndrome (IBS-C)

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

Unlock Additional Data

Additional Data Available

Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Learn more

Additional Data Available

Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more

Additional Data Available

Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more

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 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.

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

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.

Affected organisms

Not Available

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.
Not Available
Food Interactions: Not Available

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

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:28301096]
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. [PubMed:26065434]
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:28339149]
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. [PubMed:24622516]
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. [PubMed:25404658]
FDA Approved Drugs: Tenapanor [Link]

External Links

PubChem Compound: 71587953
PubChem Substance: 347828115
ChemSpider: 32056950
ChEMBL: CHEMBL3304485
Wikipedia: Tenapanor

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Basic Science	Healthy Volunteers	5
1	Completed	Basic Science	Healthy Volunteers Food Interaction Study	1
1	Completed	Treatment	Healthy Volunteers	3
2	Completed	Treatment	Chronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus	1
2	Completed	Treatment	End Stage Renal Disease (ESRD) / ESRD / Hemodialysis-dependent chronic kidney disease (HDD-CKD)	1
2	Completed	Treatment	Hyperphosphataemia	1
2	Recruiting	Treatment	Hyperphosphataemia	1
2, 3	Active Not Recruiting	Treatment	Hyperphosphataemia	1
2, 3	Completed	Treatment	Constipation-predominant Irritable Bowel Syndrome (IBS-C)	1
3	Active Not Recruiting	Treatment	Hyperphosphataemia	1
3	Completed	Treatment	Constipation-predominant Irritable Bowel Syndrome (IBS-C)	2
3	Completed	Treatment	Hyperphosphataemia	1
3	Recruiting	Treatment	Constipation-predominant Irritable Bowel Syndrome (IBS-C)	1
4	Enrolling by Invitation	Treatment	End Stage Renal Disease (ESRD) / Hyperphosphataemia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Tablet	Oral	53.2 mg/1

Prices

Not Available

Patents

Not Available

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	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

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 / Benzenesulfonamide / Benzenesulfonyl group / Aralkylamine / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Organosulfonic acid amide / Organic sulfonic acid or derivatives
show 21 more
Molecular Framework: Aromatic heteropolycyclic compounds
External Descriptors: Not Available

Targets

Details1. Sodium/hydrogen exchanger 3

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

FDA Approved Drugs: Tenapanor [Link]

Enzymes

Details1. Cytochrome P450 3A4

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

FDA Approved Drugs: Tenapanor [Link]

Details2. Cytochrome P450 3A5

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

FDA Approved Drugs: Tenapanor [Link]

Drug created on October 20, 2016 14:45 / Updated on December 02, 2019 09:10

Tenapanor

Identification

Structure for Tenapanor (DB11761)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Enzymes

References

References