Plecanatide

Identification

Name

Plecanatide

Accession Number

DB13170

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

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 1681.89
Monoisotopic: 1680.625200237
Chemical Formula: C₆₅H₁₀₄N₁₈O₂₆S₄

Synonyms

Guanilib
Plecanatide

Pharmacology

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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

Chronic idiopathic constipation (CIC)

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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.

Target	Actions	Organism
AGuanylate cyclase soluble subunit alpha-2	agonist	Humans

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.

Adverse Effects

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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

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.

Drug	Interaction
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Acetazolamide	The risk or severity of adverse effects can be increased when Acetazolamide is combined with Plecanatide.
Aclidinium	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Aclidinium.
Alfentanil	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Alfentanil.
Alloin	The risk or severity of adverse effects can be increased when Plecanatide is combined with Alloin.
Amantadine	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Amantadine.
Amiloride	The risk or severity of adverse effects can be increased when Amiloride is combined with Plecanatide.
Amiodarone	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Amiodarone.
Amitriptyline	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Amitriptyline.
Amlodipine	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Amlodipine.
Amobarbital	The therapeutic efficacy of Plecanatide can be decreased when used in combination with Amobarbital.

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Food Interactions

Take with or without food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Trulance	Tablet		Oral	Bausch Health, Canada Inc.	Not applicable	Not applicable
Trulance Immediate release	Tablet	3 mg/1	Oral	Synergy Pharmaceuticals Inc.	2017-02-21	Not applicable
Trulance Immediate release	Tablet	3 mg/1	Oral	Salix Pharmaceuticals Inc.	2017-02-21	Not applicable

Chemical Identifiers

UNII: 7IK8Z952OK
CAS number: 467426-54-6
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@@]12CSSC[C@H](NC(=O)CNC(=O)[C@@]([H])(NC(=O)[C@]([H])(CSSC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC2=O)C(C)C)C(C)C)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O

References

General References

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]
Drug Information [Link]
Medscape [Link]
FDA label [Link]

External Links

PubChem Compound: 70693500
PubChem Substance: 347829276
ChemSpider: 28530494
RxNav: 1873752
ChEMBL: CHEMBL2103867
Wikipedia: Plecanatide

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Chronic idiopathic constipation (CIC)	3
3	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1
3	Completed	Treatment	Irritable Bowel Syndrome Characterized by Constipation	2
2	Completed	Treatment	Chronic idiopathic constipation (CIC)	1
2	Completed	Treatment	Irritable Bowel Syndrome Characterized by Constipation	1
2	Recruiting	Treatment	Constipation-predominant Irritable Bowel Syndrome (IBS-C)	1
2, 3	Completed	Treatment	Chronic idiopathic constipation (CIC)	1
Not Available	Completed	Not Available	Chronic idiopathic constipation (CIC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral
Tablet	Oral	3 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US7799897	No	2010-09-21	2022-06-09
US7041786	No	2006-05-09	2023-03-25
US9616097	No	2017-04-11	2032-07-02
US8637451	No	2014-01-28	2022-03-28
US9610321	No	2017-04-04	2031-09-11
US9919024	No	2018-03-20	2031-09-15
US9925231	No	2018-03-27	2031-09-15
US10011637	No	2018-07-03	2034-06-05

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.25 mg/mL	ALOGPS
logP	-1.4	ALOGPS
logP	3.71	ChemAxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	2.43	ChemAxon
Physiological Charge	-8	ChemAxon
Hydrogen Acceptor Count	44	ChemAxon
Hydrogen Donor Count	25	ChemAxon
Polar Surface Area	772.46 Å²	ChemAxon
Rotatable Bond Count	28	ChemAxon
Refractivity	427.55 m³·mol^-1	ChemAxon
Polarizability	164.58 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	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

Targets

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Details1. Guanylate cyclase soluble subunit alpha-2

Kind: Protein
Organism: Humans
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 21:46 / Updated on February 21, 2021 18:54

Plecanatide

Identification

Structure for Plecanatide (DB13170)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets