Identification

Name
Linaclotide
Accession Number
DB08890  (DB05566)
Type
Small Molecule
Groups
Approved
Description

Linaclotide is an orally administered, peptide agonist of guanylate cyclase 2C for the treatment of irritable bowel syndrome. Chemically, it is a heterodetic cyclic peptide and consists of fourteen amino acids. The protein sequence is as follows: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. There are three disulfide bonds which are located between Cys1 and Cys6; between Cys2 and Cys10; and between Cys5 and Cys13. FDA approved on August 30, 2012.

Structure
Thumb
Synonyms
  • Cys cys glu tyr cys cys asn pro ala cys thr gly cys tyr (disulfide bridge: 1-6; 2-10; 5-13)
  • L-Cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclic (1->6),(2->10),(5->13)-tris(disulfide)
External IDs
ASP-0456 / ASP0456 / MD-1100
Product Ingredients
IngredientUNIICASInChI Key
Linaclotide AcetateNSF067KU1M851199-60-5KWFNVZFWXXEJKL-YZDVLOIKSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ConstellaCapsule290 microgramsOralAllergan Pharmaceuticals International Limited2012-11-26Not applicableEu
ConstellaCapsule145 mcgOralForest Laboratories2014-04-29Not applicableCanada
ConstellaCapsule290 microgramsOralAllergan Pharmaceuticals International Limited2012-11-26Not applicableEu
ConstellaCapsule290 microgramsOralAllergan Pharmaceuticals International Limited2012-11-26Not applicableEu
ConstellaCapsule290 microgramsOralAllergan Pharmaceuticals International Limited2012-11-26Not applicableEu
ConstellaCapsule290 mcgOralForest Laboratories2014-12-17Not applicableCanada
ConstellaCapsule72 mcgOralForest Laboratories2018-04-02Not applicableCanada
LinzessCapsule, gelatin coated72 ug/1OralAllergan2017-01-30Not applicableUs
LinzessCapsule, gelatin coated145 ug/1OralAvera McKennan Hospital2015-06-04Not applicableUs69189 120220180907 15195 h7ajiq
LinzessCapsule, gelatin coated290 ug/1OralAllergan2012-09-08Not applicableUs
International/Other Brands
Linzess
Categories
UNII
N0TXR0XR5X
CAS number
851199-59-2
Weight
Average: 1526.736
Monoisotopic: 1525.389918805
Chemical Formula
C59H79N15O21S6
InChI Key
KXGCNMMJRFDFNR-WDRJZQOASA-N
InChI
InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1
IUPAC Name
(2S)-2-{[(1R,4S,7S,13S,16R,21R,24R,27S,30S,33R,38R,44S)-21-amino-13-(carbamoylmethyl)-27-(2-carboxyethyl)-44-[(1R)-1-hydroxyethyl]-30-[(4-hydroxyphenyl)methyl]-4-methyl-3,6,12,15,22,25,28,31,40,43,46,51-dodecaoxo-18,19,35,36,48,49-hexathia-2,5,11,14,23,26,29,32,39,42,45,52-dodecaazatetracyclo[22.22.4.2¹⁶,³³.0⁷,¹¹]dopentacontan-38-yl]formamido}-3-(4-hydroxyphenyl)propanoic acid
SMILES
[H][C@]1(CSSC[C@]2([H])NC(=O)[C@H](CC3=CC=C(O)C=C3)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]3CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSSC[C@H](N)C(=O)N3)NC2=O)C(=O)N[C@@]([H])([C@@H](C)O)C(=O)NCC(=O)N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O

Pharmacology

Indication

Treatment of irritable bowel syndrome (IBS) with constipation and chronic idiopathic constipation.

Associated Conditions
Pharmacodynamics

Changes in the appearance and consistency of stools as measured by the Bristol Stool Form Scale (BSFS) have been noted after taking linaclotide.

Mechanism of action

Linaclotide is an agonist of guanylate cyclase-C (GC-C). Once linaclotide and its active metabolite binds to GC-C, it has local effect on the luminal surface of the intestinal epithelium. Activation of GC-C by linaclotide results in the intra- and extracellular increase of cyclic guanosine monophosphate concentrations (cGMP). This elevation of cGMP levels stimulates the secretion of chloride and bicarbonate into the intestinal lumen via activation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Ultimately, linaclotide helps patients with IBS (especially with constipation) as GI transit is accelerated and the release of intestinal fluid is increased. In animal models, a decrease in visceral pain after administration of linaclotide may be observed. A decrease in the activity of pain-sensing nerves occurs as a result of an increase in extracellular cGMP.

TargetActionsOrganism
AHeat-stable enterotoxin receptor
agonist
Human
Absorption

When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mcg or 290 mcg were administered.

Volume of distribution

Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.

Protein binding
Not Available
Metabolism

Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite, MM-419447, by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Route of elimination

Linaclotide is eliminated fecally (3 - 5% as active metabolites). However most of the dose undergoes proteolysis (processes include reduction of disulfide bonds) in the intestine before being excreted via feces.

Half life

Because linaclotide is not systemically absorbed, half life cannot be calculated.

Clearance
Not Available
Toxicity

Most common adverse reactions (incidence of at least 2%) reported in IBS-C or CIC patients are diarrhea, abdominal pain, flatulence and abdominal distension.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Linaclotide.
AgmatineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Agmatine.
AlfentanilThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Alfentanil.
Aluminum hydroxideThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Aluminum hydroxide.
AmantadineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amantadine.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Linaclotide.
AmiodaroneThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amiodarone.
AmitriptylineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amitriptyline.
AmlodipineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amlodipine.
AmoxapineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amoxapine.
Food Interactions
  • Even when taken with food, linaclotide does not reach detectable levels in the plasma. However, when taken with a high fat meal, one may observe looser stools and a higher stool frequency.

References

General References
  1. Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, Solinga RM, Tobin JV, Wakefield JD, Kurtz CB, Currie MG: Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013 Jan;344(1):196-206. doi: 10.1124/jpet.112.199430. Epub 2012 Oct 22. [PubMed:23090647]
External Links
KEGG Drug
D09355
PubChem Compound
16158208
PubChem Substance
175427136
ChemSpider
17314504
ChEBI
68551
ChEMBL
CHEMBL3301675
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Linaclotide
ATC Codes
A06AX04 — Linaclotide
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (226 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of ASP04562
1CompletedBasic ScienceColorectal Cancers / Healthy, no Evidence of Disease1
1RecruitingOtherBreast Feeding / Irritable Bowel Syndrome (IBS) / Occasional Constipation1
2CompletedTreatmentChronic Constipation2
2CompletedTreatmentConstipation Predominant Irritable Bowel Syndrome2
2CompletedTreatmentConstipation-predominant Irritable Bowel Syndrome (IBS-C)1
2CompletedTreatmentFunctional Constipation in Children Ages 6-17 Years1
2CompletedTreatmentOpioid Induced Constipation (OIC)1
2RecruitingTreatmentConstipation Predominant Irritable Bowel Syndrome1
3CompletedTreatmentChronic Constipation3
3CompletedTreatmentChronic Constipation / Constipation Predominant Irritable Bowel Syndrome2
3CompletedTreatmentChronic Constipation / Occasional Constipation1
3CompletedTreatmentChronic Idiopathic Constipation1
3CompletedTreatmentIrritable Bowel Syndrome Characterized by Constipation1
3CompletedTreatmentIrritable Bowel Syndrome With Constipation (IBS-C)2
3RecruitingTreatmentIrritable Bowel Syndrome Characterized by Constipation1
4Active Not RecruitingTreatmentChronic Constipation / Chronic Constipation in Diabetic Patients / Diabete Mellitus1
4Active Not RecruitingTreatmentChronic Idiopathic Constipation / Constipation Predominant Irritable Bowel Syndrome1
4CompletedTreatmentCrohn's Disease (CD) / Gastrointestinal Bleedings / Ulcerative Colitis (UC)1
4RecruitingTreatmentIrritable Bowel Syndrome Characterized by Constipation1
Not AvailableCompletedOtherIrritable Bowel Syndrome With Constipation (IBS-C)1
Not AvailableCompletedTreatmentChronic Idiopathic Constipation1
Not AvailableEnrolling by InvitationDiagnosticIrritable Bowel Syndrome (IBS)1
Not AvailableRecruitingNot AvailableIrritable Bowel Syndrome With Constipation (IBS-C)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral145 mcg
CapsuleOral290 mcg
CapsuleOral290 micrograms
CapsuleOral72 mcg
Capsule, gelatin coatedOral145 ug/1
Capsule, gelatin coatedOral290 ug/1
Capsule, gelatin coatedOral72 ug/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8110553No2004-01-282024-01-28Us
US8748573No2011-06-202031-06-20Us
US7304036No2006-08-302026-08-30Us
US7704947No2004-01-282024-01-28Us
US8080526No2004-01-282024-01-28Us
US8933030No2011-02-172031-02-17Us
US7371727No2004-01-282024-01-28Us
US8802628No2011-07-242031-07-24Us
US7745409No2004-01-282024-01-28Us
US9708371No2013-08-162033-08-16Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly soluble FDA
Predicted Properties
PropertyValueSource
Water Solubility0.701 mg/mLALOGPS
logP-1.5ALOGPS
logP-11ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)3.06ChemAxon
pKa (Strongest Basic)7.65ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count22ChemAxon
Hydrogen Donor Count19ChemAxon
Polar Surface Area573.91 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity368 m3·mol-1ChemAxon
Polarizability145.88 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6643
Blood Brain Barrier-0.9796
Caco-2 permeable-0.786
P-glycoprotein substrateSubstrate0.7846
P-glycoprotein inhibitor INon-inhibitor0.9096
P-glycoprotein inhibitor IINon-inhibitor0.993
Renal organic cation transporterNon-inhibitor0.8841
CYP450 2C9 substrateNon-substrate0.8072
CYP450 2D6 substrateNon-substrate0.7947
CYP450 3A4 substrateSubstrate0.5121
CYP450 1A2 substrateNon-inhibitor0.9053
CYP450 2C9 inhibitorNon-inhibitor0.8507
CYP450 2D6 inhibitorNon-inhibitor0.8759
CYP450 2C19 inhibitorNon-inhibitor0.8164
CYP450 3A4 inhibitorNon-inhibitor0.8592
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8908
Ames testNon AMES toxic0.6831
CarcinogenicityNon-carcinogens0.7978
BiodegradationNot ready biodegradable0.9839
Rat acute toxicity3.0981 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9284
hERG inhibition (predictor II)Inhibitor0.5115
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Cyclic peptides / Tyrosine and derivatives / Phenylalanine and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Phenylpropanoic acids / Amphetamines and derivatives / 1-hydroxy-2-unsubstituted benzenoids / Dicarboxylic acids and derivatives / Tertiary carboxylic acid amides
show 14 more
Substituents
Polypeptide / Cyclic alpha peptide / Tyrosine or derivatives / Phenylalanine or derivatives / N-acyl-alpha amino acid or derivatives / N-acyl-alpha-amino acid / N-acyl-l-alpha-amino acid / Alpha-amino acid amide / 3-phenylpropanoic-acid / Alpha-amino acid or derivatives
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
heterodetic cyclic peptide (CHEBI:68551)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Toxic substance binding
Specific Function
Receptor for the E.coli heat-stable enterotoxin (E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GC-C). Also activated by the endogenous peptides guany...
Gene Name
GUCY2C
Uniprot ID
P25092
Uniprot Name
Heat-stable enterotoxin receptor
Molecular Weight
123401.73 Da
References
  1. Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, Solinga RM, Tobin JV, Wakefield JD, Kurtz CB, Currie MG: Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013 Jan;344(1):196-206. doi: 10.1124/jpet.112.199430. Epub 2012 Oct 22. [PubMed:23090647]

Drug created on May 30, 2013 00:18 / Updated on October 16, 2018 08:40