Tegaserod

Identification

Name

Tegaserod

Accession Number

DB01079  (APRD00096)

Type

Small Molecule

Groups

Approved, Investigational, Withdrawn

Description

Tegaserod is a 5-HT4 agonist manufactured by Novartis and used for the management of irritable bowel syndrome and constipation. Its use was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating and constipation associated with irritable bowel syndrome. On March 30, 2007, the U.S. Food and Drug Administration requested that Novartis withdraw Zelnorm from shelves. The FDA alleges a relationship between prescriptions of the drug and increased risks of heart attack or stroke. [Wikipedia]

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Tegaserod (DB01079)

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Synonyms

• 1-(((5-Methoxyindol-3-yl)methylene)amino)-3-pentylguanidine
• Tegaserod
• tégasérod
• tegaserodum

External IDs

SDZ HTF 919

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tegaserod maleate	E5XNT3RF5A	189188-57-6	CPDDZSSEAVLMRY-FEQFWAPWSA-N

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Zelnorm	Tablet	6 mg/1	Oral	Novartis	2002-07-24	2009-01-31
Zelnorm	Tablet	2 mg/1	Oral	Novartis	2002-07-24	2010-05-31
Zelnorm	Tablet	6 mg/1	Oral	Novartis	2002-07-24	2008-06-30

International/Other Brands

Zelmac / Zelnorm

Categories

• Alimentary Tract and Metabolism
• Central Nervous System Depressants
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (weak)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (moderate)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inhibitors
• Drugs for Constipation
• Gastrointestinal Agents
• Laxatives
• Neurotransmitter Agents
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin 4 Receptor Antagonists
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Agents
• Serotonin Receptor Agonists
• Serotonin Receptor Antagonists
• Serotonin-4 Receptor Antagonist

UNII

458VC51857

CAS number

145158-71-0

Weight

Average: 301.394
Monoisotopic: 301.190260381

Chemical Formula

C₁₆H₂₃N₅O

InChI Key

IKBKZGMPCYNSLU-RGVLZGJSSA-N

InChI

InChI=1S/C16H23N5O/c1-3-4-5-8-18-16(17)21-20-11-12-10-19-15-7-6-13(22-2)9-14(12)15/h6-7,9-11,19H,3-5,8H2,1-2H3,(H3,17,18,21)/b20-11+

IUPAC Name

N'-[(E)-[(5-methoxy-1H-indol-3-yl)methylidene]amino]-N-pentylguanidine

SMILES

CCCCCNC(=N)N\N=C\C1=CNC2=C1C=C(OC)C=C2

Pharmacology

Indication

Provides relief from the symptoms of irritable bowel syndrome including chronic idiopathic constipation.

Pharmacodynamics

Tegaserod is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation. Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT₄) receptors in the maintenance of gastrointestinal functions in humans. 5-HT₄ receptor mRNA has been found throughout the human gastrointestinal tract.

Mechanism of action

Tegaserod is a 5-HT₄ receptor partial agonist that binds with high affinity at human 5-HT₄ receptors, whereas it has no appreciable affinity for 5-HT₃ or dopamine receptors. It has moderate affinity for 5-HT₁ receptors. Tegaserod, by acting as an agonist at neuronal 5-HT₄ receptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons. The activation of 5-HT₄ receptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity.

Target	Actions	Organism
A5-hydroxytryptamine receptor 4	antagonist partial agonist	Humans
U5-hydroxytryptamine receptor 2B	antagonist	Humans
U5-hydroxytryptamine receptor 2C	antagonist	Humans
U5-hydroxytryptamine receptor 2A	antagonist	Humans

Absorption

Rapidly absorbed after oral administration, with an absolute bioavailability of approximately 10%.

Volume of distribution

• 368 ± 223 L

Protein binding

98%

Metabolism

Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HT₄ receptors in vitro. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides.

Route of elimination

Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite.

Half life

11 ± 5 hours

Clearance

• 77 +/- 15 L/h [IV administration]

Toxicity

Oral LD₅₀ in rat is 2000 mg/kg.

Affected organisms

• Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

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

Drug	Interaction
(R)-warfarin	The metabolism of (R)-warfarin can be decreased when combined with Tegaserod.
(S)-Warfarin	The risk or severity of adverse effects can be increased when Tegaserod is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamine	The risk or severity of serotonin syndrome can be increased when Tegaserod is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of serotonin syndrome can be increased when Tegaserod is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-Methylenedioxyamphetamine	The risk or severity of serotonin syndrome can be increased when Tegaserod is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of serotonin syndrome can be increased when Tegaserod is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarin	The risk or severity of adverse effects can be increased when Tegaserod is combined with 4-hydroxycoumarin.
4-Methoxyamphetamine	The risk or severity of adverse effects can be increased when Tegaserod is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamine	The risk or severity of serotonin syndrome can be increased when Tegaserod is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanine	The metabolism of 6-O-benzylguanine can be decreased when combined with Tegaserod.

Food Interactions

• Take before a meal, to increase absorption, take 30 minutes before a meal.

References

Synthesis Reference

Sundaram Venkataraman, Srinivasulu Gudipati, Brahmeshwararao Mandava Venkata Naga, Goverdhan Banda, Radhakrishna Singamsetty, "Process for preparing form I of tegaserod maleate." U.S. Patent US20050272802, issued December 08, 2005.

US20050272802

General References

Not Available

External Links

KEGG Drug

D06056

PubChem Compound

5362436

PubChem Substance

46506519

ChemSpider

10609889

BindingDB

79022

ChEBI

51043

ChEMBL

CHEMBL76370

Therapeutic Targets Database

DAP001526

PharmGKB

PA130413154

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Tegaserod

ATC Codes

A06AX06 — Tegaserod

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

FDA label

Download (634 KB)

MSDS

Download (58.1 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Completed	Treatment	Symptomatic Gastroespohageal Reflux Disease	1
2	Terminated	Not Available	Diabetic Gastropathy	1
2, 3	Terminated	Treatment	Occasional Constipation	1
3	Completed	Treatment	Chronic Constipation	1
3	Completed	Treatment	Gastro-esophageal Reflux Disease (GERD)	2
3	Completed	Treatment	Heartburn / Indigestion	1
3	Completed	Treatment	Indigestion	5
3	Completed	Treatment	Occasional Constipation	1
3	Terminated	Treatment	Constipation Predominant / Irritable Bowel Syndrome (IBS-C)	1
3	Terminated	Treatment	Opioid Induced Constipation (OIC)	2
4	Completed	Treatment	Chronic Constipation	1
4	Completed	Treatment	IBS-C and IBS With Mixed Bowel Habits	1
4	Completed	Treatment	Occasional Constipation	1
4	Terminated	Treatment	Chronic Constipation	1
4	Terminated	Treatment	Diabetes Mellitus (DM) / Gastroparesis	1
4	Withdrawn	Treatment	Constipation and Dyspepsia	1
Not Available	No Longer Available	Not Available	Chronic Idiopathic Constipation / Constipation-predominant Irritable Bowel Syndrome (IBS-C)	1
Not Available	Terminated	Treatment	Disease, Chronic / Occasional Constipation	1
Not Available	Unknown Status	Treatment	Occasional Constipation	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

• Murfreesboro Pharmaceutical Nursing Supply
• Novartis AG

Dosage forms

Form	Route	Strength
Tablet	Oral	2 mg/1
Tablet	Oral	6 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5510353	No	1996-04-23	2013-04-26

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	155 °C	Not Available
logP	2.6	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0288 mg/mL	ALOGPS
logP	2.76	ALOGPS
logP	2.95	ChemAxon
logS	-4	ALOGPS
pKa (Strongest Acidic)	15.24	ChemAxon
pKa (Strongest Basic)	8.5	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	4	ChemAxon
Polar Surface Area	85.29 Å2	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	110.25 m3·mol-1	ChemAxon
Polarizability	34.96 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9973
Blood Brain Barrier	+	0.7842
Caco-2 permeable	-	0.5939
P-glycoprotein substrate	Substrate	0.921
P-glycoprotein inhibitor I	Non-inhibitor	0.8978
P-glycoprotein inhibitor II	Non-inhibitor	0.959
Renal organic cation transporter	Inhibitor	0.5488
CYP450 2C9 substrate	Non-substrate	0.8522
CYP450 2D6 substrate	Non-substrate	0.5492
CYP450 3A4 substrate	Non-substrate	0.6565
CYP450 1A2 substrate	Non-inhibitor	0.53
CYP450 2C9 inhibitor	Non-inhibitor	0.7096
CYP450 2D6 inhibitor	Non-inhibitor	0.7807
CYP450 2C19 inhibitor	Non-inhibitor	0.6372
CYP450 3A4 inhibitor	Non-inhibitor	0.8954
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.7654
Ames test	Non AMES toxic	0.5434
Carcinogenicity	Non-carcinogens	0.7783
Biodegradation	Not ready biodegradable	0.9972
Rat acute toxicity	2.6038 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.5123
hERG inhibition (predictor II)	Non-inhibitor	0.8334

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 indoles. These are compounds containing an indole moiety, which consists of pyrrole ring fused to benzene to form 2,3-benzopyrrole.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Indoles and derivatives

Sub Class

Indoles

Direct Parent

Indoles

Alternative Parents

Anisoles / Alkyl aryl ethers / Substituted pyrroles / Heteroaromatic compounds / Guanidines / Carboximidamides / Azacyclic compounds / Organopnictogen compounds / Imines / Hydrocarbon derivatives

Substituents

Indole / Anisole / Alkyl aryl ether / Substituted pyrrole / Benzenoid / Pyrrole / Heteroaromatic compound / Guanidine / Azacycle / Ether

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

guanidines, indoles, carboxamidine, hydrazines (CHEBI:51043)

Drug created on June 13, 2005 07:24 / Updated on December 16, 2018 06:46