Identification

Name
Plecanatide
Accession Number
DB13170  (DB06377)
Type
Small Molecule
Groups
Approved, Investigational
Description

Plecanatide is a drug approved in January 2017 by the FDA for the treatment of chronic idiopathic constipation (CIC). It should not be used in children less than six years of age, and should be avoided in patients six years to 18 years of age

Structure
Thumb
Synonyms
  • Guanilib
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Trulance Immediate releaseTablet3 mg/1OralSynergy Pharmaceuticals Inc.2017-02-21Not applicableUs
Categories
UNII
7IK8Z952OK
CAS number
467426-54-6
Weight
Average: 1681.89
Monoisotopic: 1680.625200237
Chemical Formula
C65H104N18O26S4
InChI Key
NSPHQWLKCGGCQR-DLJDZFDSSA-N
InChI
InChI=1S/C65H104N18O26S4/c1-25(2)15-34-55(98)80-41-24-113-110-21-38(58(101)77-37(65(108)109)16-26(3)4)71-44(87)20-69-62(105)50(30(10)84)83-61(104)40(78-51(94)29(9)70-63(106)48(27(5)6)81-57(100)35(18-43(68)86)76-64(107)49(28(7)8)82-60(41)103)23-112-111-22-39(59(102)73-32(53(96)75-34)11-13-45(88)89)79-54(97)33(12-14-46(90)91)72-56(99)36(19-47(92)93)74-52(95)31(66)17-42(67)85/h25-41,48-50,84H,11-24,66H2,1-10H3,(H2,67,85)(H2,68,86)(H,69,105)(H,70,106)(H,71,87)(H,72,99)(H,73,102)(H,74,95)(H,75,96)(H,76,107)(H,77,101)(H,78,94)(H,79,97)(H,80,98)(H,81,100)(H,82,103)(H,83,104)(H,88,89)(H,90,91)(H,92,93)(H,108,109)/t29-,30+,31-,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,48-,49-,50-/m0/s1
IUPAC Name
(4S)-4-{[(2S)-2-{[(2S)-2-amino-1-hydroxy-3-(C-hydroxycarbonimidoyl)propylidene]amino}-3-carboxy-1-hydroxypropylidene]amino}-4-{[(1R,4S,7S,10S,13S,16R,19S,22S,25R,32S,38R)-38-{[(1S)-1-carboxy-3-methylbutyl]-C-hydroxycarbonimidoyl}-22-(2-carboxyethyl)-3,6,9,12,15,18,21,24,30,33,36-undecahydroxy-10-[(C-hydroxycarbonimidoyl)methyl]-32-[(1R)-1-hydroxyethyl]-4-methyl-19-(2-methylpropyl)-7,13-bis(propan-2-yl)-27,28,40,41-tetrathia-2,5,8,11,14,17,20,23,31,34,37-undecaazabicyclo[14.13.13]dotetraconta-2,5,8,11,14,17,20,23,30,33,36-undecaen-25-yl]-C-hydroxycarbonimidoyl}butanoic acid
SMILES
[H][C@](C)(O)[C@]1([H])N=C(O)[C@]2([H])CSSC[C@]([H])(N=C(O)[C@]([H])(CCC(O)=O)N=C(O)[C@]([H])(CC(O)=O)N=C(O)[C@@]([H])(N)CC(O)=N)C(O)=N[C@@]([H])(CCC(O)=O)C(O)=N[C@@]([H])(CC(C)C)C(O)=N[C@@]([H])(CSSC[C@]([H])(N=C(O)CN=C1O)C(O)=N[C@@]([H])(CC(C)C)C(O)=O)C(O)=N[C@@]([H])(C(C)C)C(O)=N[C@@]([H])(CC(O)=N)C(O)=N[C@@]([H])(C(C)C)C(O)=N[C@@]([H])(C)C(O)=N2

Pharmacology

Indication

Plecanatide stimulates intestinal fluid secretions in the gastrointestinal tract to support regular bowel function. Plecanatide, taken orally once daily, works locally in the upper GI tract to stimulate secretion of intestinal fluid and support regular bowel function.

Associated Conditions
Pharmacodynamics

Food Effect Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of 9 mg (3 times the recommended dose). In clinical studies, Plecanatide was administered with or without food.

Mechanism of action

Guanylate cyclase C (GC-C) agonist Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of intestinal epithelial cells; GC-C activation leads to increased cyclic guanosine monophosphate (cGMP), which, in turn, stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, plecanatide has been shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency. In an animal model of visceral pain, plecanatide reduced abdominal muscle contractions, a measure of intestinal pain. The mechanism has not been studied.

TargetActionsOrganism
AGuanylate cyclase soluble subunit alpha-2
agonist
Human
Absorption

Plecanatide is minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t½) cannot be calculated.

Volume of distribution

Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral dose of 3 mg. Therefore, the volume of distribution can not be calculated.

Protein binding

Plecanatide exhibits little to no binding to human serum albumin or human α-1-acid glycoprotein.

Metabolism

Plecanatide is metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Route of elimination

No excretion studies have been conducted in humans. Plecanatide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses.

Half life

half-life (t½) cannot be calculated due to negligible systemic absorbance

Clearance

No excretion studies have been conducted in humans.

Toxicity

Single oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days 7 and 14, respectively (human age equivalent of approximately 1 month to less than 2 years).

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

Interactions

Drug Interactions
DrugInteraction
AgmatineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Agmatine.
Aluminum hydroxideThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Aluminum hydroxide.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Plecanatide.
AmiodaroneThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Amiodarone.
AmlodipineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Amlodipine.
AranidipineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Aranidipine.
AtropineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Atropine.
AzelnidipineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Azelnidipine.
BarnidipineThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Barnidipine.
BencyclaneThe therapeutic efficacy of Plecanatide can be decreased when used in combination with Bencyclane.
Food Interactions
Not Available

References

General References
  1. Thomas RH, Luthin DR: Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents. Pharmacotherapy. 2015 Jun;35(6):613-30. doi: 10.1002/phar.1594. Epub 2015 May 27. [PubMed:26016701]
  2. Drug Information [Link]
  3. Medscape [Link]
  4. FDA label [Link]
External Links
PubChem Compound
70693500
PubChem Substance
347829276
ChemSpider
28530494
ChEMBL
CHEMBL2103867
Wikipedia
Plecanatide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentChronic Idiopathic Constipation / Constipation Predominant Irritable Bowel Syndrome1
2CompletedTreatmentIrritable Bowel Syndrome Characterized by Constipation1
2RecruitingTreatmentConstipation Predominant Irritable Bowel Syndrome1
2, 3CompletedTreatmentChronic Idiopathic Constipation1
3CompletedTreatmentChronic Idiopathic Constipation3
3CompletedTreatmentIrritable Bowel Syndrome (IBS)1
3CompletedTreatmentIrritable Bowel Syndrome Characterized by Constipation2
Not AvailableRecruitingNot AvailableChronic Idiopathic Constipation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral3 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7799897No2002-06-092022-06-09Us
US7041786No2003-03-252023-03-25Us
US9616097No2012-07-022032-07-02Us
US8637451No2002-03-282022-03-28Us
US9610321No2011-09-112031-09-11Us
US9919024No2011-09-152031-09-15Us
US9925231No2011-09-152031-09-15Us
US10011637No2014-06-052034-06-05Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.165 mg/mLALOGPS
logP0.64ALOGPS
logP3.71ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)2.43ChemAxon
Physiological Charge-8ChemAxon
Hydrogen Acceptor Count44ChemAxon
Hydrogen Donor Count25ChemAxon
Polar Surface Area772.46 Å2ChemAxon
Rotatable Bond Count28ChemAxon
Refractivity427.55 m3·mol-1ChemAxon
Polarizability164.58 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

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 / Glutamic acid and derivatives / Asparagine and derivatives / Aspartic acid and derivatives / Leucine and derivatives / Tetracarboxylic acids and derivatives / N-acyl-L-alpha-amino acids / Macrolactams / Alpha amino acid amides / N-acyl amines
show 12 more
Substituents
Polypeptide / Cyclic alpha peptide / Glutamic acid or derivatives / Asparagine or derivatives / Aspartic acid or derivatives / Leucine or derivatives / N-acyl-alpha amino acid or derivatives / N-acyl-alpha-amino acid / N-acyl-l-alpha-amino acid / Macrolactam
show 31 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Heme binding
Specific Function
Has guanylyl cyclase on binding to the beta-1 subunit.Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.
Gene Name
GUCY1A2
Uniprot ID
P33402
Uniprot Name
Guanylate cyclase soluble subunit alpha-2
Molecular Weight
81749.185 Da

Drug created on February 27, 2017 14:46 / Updated on August 02, 2018 06:48