Identification

Name
Prucalopride
Accession Number
DB06480
Type
Small Molecule
Groups
Approved
Description

Prucalopride is a dihydrobenzofurancarboxamide derivative from the benzofurane family that selectively stimulates 5-HT4 receptors and thus, it presents enterokinetic properties.[2] The high selectivity of prucalopride allowed further development as it prevented the cardiac adverse reactions observed due to non-target effects of precedent therapies.[5] Prucalopride was developed by Shire Development LLC and approved for use in Europe in 2009,[1] in Canada on December 7, 2011 and by the FDA on December 17, 2018.[7]

Structure
Thumb
Synonyms
  • Prucaloprida
  • Prucalopride
External IDs
R-093877 / R093877
Product Ingredients
IngredientUNIICASInChI Key
Prucalopride hydrochlorideM8IYX9Z79V179474-80-7KKMOQGWTJRGLNN-UHFFFAOYSA-N
Prucalopride succinate4V2G75E1CK179474-85-2QZRSNVSQLGRAID-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MotegrityTablet, film coated2 mg/1OralShire US Manufacturing Inc.2018-12-14Not applicableUs
MotegrityTablet, film coated1 mg/1OralShire US Manufacturing Inc.2018-12-14Not applicableUs
ResotranTablet2 mgOralJanssen Pharmaceuticals2012-01-12Not applicableCanada
ResotranTablet1 mgOralJanssen Pharmaceuticals2012-01-12Not applicableCanada
International/Other Brands
Resolor (Shire Pharmaceuticals Ireland Ltd)
Categories
UNII
0A09IUW5TP
CAS number
179474-81-8
Weight
Average: 367.87
Monoisotopic: 367.1662694
Chemical Formula
C18H26ClN3O3
InChI Key
ZPMNHBXQOOVQJL-UHFFFAOYSA-N
InChI
InChI=1S/C18H26ClN3O3/c1-24-9-2-6-22-7-3-12(4-8-22)21-18(23)14-11-15(19)16(20)13-5-10-25-17(13)14/h11-12H,2-10,20H2,1H3,(H,21,23)
IUPAC Name
4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
SMILES
COCCCN1CCC(CC1)NC(=O)C1=C2OCCC2=C(N)C(Cl)=C1

Pharmacology

Indication

Prucalopride is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.[8]

CIC is one of the most common chronic functional gastrointestinal disorders worldwide. The diagnosis of this agent is very hard and it can be confirmed if the patient experience at least two of the following:

-Straining during more than 25% of the bowel movements.

-Lumpy or hard stools in 25% of the bowel movements.

-Sensation of incomplete evacuation in more than 25% of all bowel movements.

-Sensation of anorectal blockage or obstruction in more than 25% of the bowel movements.

-Manual maneuvers required in more than 25% of the bowel movements.

-Fewer than 3 bowel movements per week.[9]

Associated Conditions
Pharmacodynamics

In animal studies, prucalopride induced a dose-dependent stimulation of contractile activity in the proximal colon and inhibition of the contractility in the distal colon.[4] As well it has been shown that prucalopride stimulates and amplifies giant migratory contraction which is the high-amplitude type of contraction that initiates the urge to defecate. Thus, prucalopride not only accelerates the colonic transit but also accelerates gastric emptying and small bowel transit.[2]

In supratherapeutic concentrations, prucalopride can be observed to interact with hERG potassium channels and L-type calcium channels.[2]

In clinical trials, prucalopride showed to significantly increase the spontaneous bowel movements with a standardized mean difference of about 0.5 after the use of 1 mg when compared with the placebo group.[5] In this studies as well, it was observed a numerical improvement in mean colonic transit time and a significant increase in spontaneous complete bowel movement without marked changes in the anorectal function.[5]

In phase III clinical trials, 86% of the tested individuals opted to continue with the open-label study and based on Patients Assessments, 67% of the patients increase more than one point improvement in their satisfaction.[5]

In the final set of clinical trials for approval, there was a significant increase in the number of patients that reached over 3 complete spontaneous bowel movements per week when compared with the placebo.[8]

Mechanism of action

Prucalopride acts as a selective stimulator of the 5-HT4 receptors while having no interaction with hERG channel or 5-HT1 receptors which reduces significantly the cardiovascular risk found in other similar drugs.[1]

5-HT4 receptors can be found throughout the gastrointestinal tract primarily in smooth muscle cells, enterochromaffin cells, and myenteric plexus. Its activation produces the release of acetylcholine which is the major excitatory neurotransmitter in the GI tract.[2]

Hence, prucalopride stimulates motility by interacting specifically with 5-HT4 receptors in the GI tract which causes a release of acetylcholine and further contraction of the muscle layer of the colon and relaxation of the circular muscle layer leading to the propulsion of luminal content.[3]

TargetActionsOrganism
A5-hydroxytryptamine receptor 4
agonist
Humans
Absorption

Prucalopride is well absorbed and it reaches maximum plasma concentration of 3.79ng/ml with a tmax of 2.77 hours after initial administration. It presents an AUC of 96.5 mn.h/ml.[6] The bioavailability of prucalopride is of over 90% and this bioavailability does not get influenced by the ingestion of food.[10]

Volume of distribution

The mean volume of distribution of prucalopride is registered to be 623 L.[6]

Protein binding

The plasma protein binding of prucalopride is of 30%.[10]

Metabolism

Prucalopride is not extensively metabolized in the body and does not interact with the enzymes of the family of the cytochrome P450 enzymes nor the P glycoprotein.[2] The metabolism of prucalopride only represents 6% of the administered dose and the remaining 94% is found as the unchanged drug.[6] From studies, it was reported the recovery of 8 metabolites being the major metabolite R107504 which is formed after the O-demethylation and oxidation of the resulting alcohol to a carboxylic acid.[10]

Route of elimination

After maximum plasma concentration, prucalopride concentration decline in a biphasic manner. Prucalopride is mainly excreted by the urine, representing 84% of the administered dose while only 13% of the dose is recovered in feces.[6]

Half life

The reported half-life of prucalopride is of around 18-20 hours.[6]

Clearance

Prucalopride renal clearance is reported to be of 17 L/h which actually exceeds the glomerular filtration rate of the kidney.[6]

Toxicity

Prucalopride is well tolerated in doses reaching 10 times the recommended therapeutic dose and signs of overdose are thought to be stared by the presence of headaches, nausea and diarrhea.[10] Carcinogenicity studies in mice indicated an increased incidence of mammary gland adenocarcinoma at a dose of 80 mg/kg/day. In rats, high doses were linked to increased incidence of benign adrenal pheochromocytoma, pituitary adenoma, pancreatic adenoma, hepatocellular adenoma and thyroid follicular tumors.[11]

For genotoxicity, prucalopride showed only one weak positive result in one of the five bacterial strain reverse mutation test at high concentrations.[11] As well, there is no evidence of adverse effects on fertility, even in high doses.[Label]

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Prucalopride.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Prucalopride.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Prucalopride.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Prucalopride.
5-androstenedioneThe metabolism of Prucalopride can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Prucalopride can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Prucalopride.
7-ethyl-10-hydroxycamptothecinThe metabolism of Prucalopride can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Prucalopride.
AbacavirAbacavir may decrease the excretion rate of Prucalopride which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH: Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53. doi: 10.1111/apt.12571. Epub 2013 Dec 5. [PubMed:24308797]
  2. Omer A, Quigley EMM: An update on prucalopride in the treatment of chronic constipation. Therap Adv Gastroenterol. 2017 Nov;10(11):877-887. doi: 10.1177/1756283X17734809. Epub 2017 Oct 16. [PubMed:29147138]
  3. Briejer MR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, Prins NH, Schuurkes JA: The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001 Jun 29;423(1):71-83. [PubMed:11438309]
  4. Briejer MR, Prins NH, Schuurkes JA: Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil. 2001 Oct;13(5):465-72. [PubMed:11696108]
  5. Sajid MS, Hebbar M, Baig MK, Li A, Philipose Z: Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. doi: 10.5056/jnm16004. [PubMed:27127190]
  6. Flach S, Scarfe G, Dragone J, Ding J, Seymour M, Pennick M, Pankratz T, Troy S, Getsy J: A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers. Clin Ther. 2016 Sep;38(9):2106-15. doi: 10.1016/j.clinthera.2016.08.003. Epub 2016 Sep 7. [PubMed:27614912]
  7. FDA reports [Link]
  8. FDA approvals [Link]
  9. Canadian Society of Intestinal Research [Link]
  10. Resotrans (prucalopride) Australian label [File]
  11. Resotrans (prucalopride) Australian data sheet [File]
External Links
PubChem Compound
3052762
PubChem Substance
310264873
ChemSpider
2314539
BindingDB
50122872
ChEBI
135552
ChEMBL
CHEMBL117287
Wikipedia
Prucalopride
ATC Codes
A06AX05 — Prucalopride
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (457 KB)
MSDS
Download (292 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableOccasional Constipation1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHepatic Impairment1
1CompletedTreatmentOccasional Constipation4
1, 2CompletedNot AvailableFunctional Constipation1
2CompletedTreatmentChronic Constipation1
2CompletedTreatmentOccasional Constipation5
2CompletedTreatmentPostoperative paralytic ileus1
2Enrolling by InvitationTreatmentIneffective Esophageal Motility / Swallowing Disorders1
2, 3RecruitingTreatmentDiabetes Mellitus (DM) / Gastroparesis1
3CompletedDiagnosticBowel preparation therapy / Colon Capsule Completion Times1
3CompletedDiagnosticColon Capsule Completion Rates / Colon Capsule Polyp Detection / Quality of Bowel Preparation for the Colon Capsule1
3CompletedTreatmentChronic Constipation2
3CompletedTreatmentFunctional Constipation1
3CompletedTreatmentMale Subjects With Chronic Constipation1
3CompletedTreatmentOccasional Constipation8
3RecruitingPreventionPostoperative Complications / Postoperative paralytic ileus / Surgery, Colorectal1
3TerminatedTreatmentNon-cancer Pain / Opioid Induced Constipation (OIC)1
4CompletedOtherChronic Constipation1
4CompletedTreatmentChronic Constipation1
4CompletedTreatmentOccasional Constipation2
4Not Yet RecruitingTreatmentCrohn's Disease (CD) / Gluten Enteropathy / Hemorrhage, Gastrointestinal / Inflammatory Bowel Diseases (IBD) / Intestinal Diseases1
4RecruitingTreatmentGastro-esophageal Reflux Disease (GERD)1
4RecruitingTreatmentGastroparesis1
4RecruitingTreatmentPostoperative paralytic ileus1
4WithdrawnNot AvailableChronic Constipation1
Not AvailableCompletedTreatmentOccasional Constipation1
Not AvailableNot Yet RecruitingBasic ScienceAntidepressive Agents / Cognition / Depression / Depressive Disorders / Molecular Mechanisms of Pharmacological Action / Moods Disorders / Psychiatric Disorder NOS1
Not AvailableSuspendedNot AvailableOccasional Constipation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral2 mg/1
TabletOral1 mg
TabletOral2 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>196 ºC'MSDS'
water solubility<1 mg/mL 'MSDS'
logP2.56 'MSDS'
pKa8.5Resotrans data sheet (measure of piperidine moiety)
Predicted Properties
PropertyValueSource
Water Solubility0.129 mg/mLALOGPS
logP2.09ALOGPS
logP0.74ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)14.64ChemAxon
pKa (Strongest Basic)8.98ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area76.82 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity100.67 m3·mol-1ChemAxon
Polarizability39.08 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 aminobenzamides. These are organic compounds containing a benzamide moiety with an amine group attached to the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Aminobenzamides
Alternative Parents
Coumarans / Alkyl aryl ethers / Piperidines / Aryl chlorides / Trialkylamines / Secondary carboxylic acid amides / Amino acids and derivatives / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds
show 5 more
Substituents
Aminobenzamide / Coumaran / Alkyl aryl ether / Aryl chloride / Aryl halide / Piperidine / Amino acid or derivatives / Carboxamide group / Secondary carboxylic acid amide / Tertiary aliphatic amine
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
Gene Name
HTR4
Uniprot ID
Q13639
Uniprot Name
5-hydroxytryptamine receptor 4
Molecular Weight
43760.975 Da
References
  1. Briejer MR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, Prins NH, Schuurkes JA: The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001 Jun 29;423(1):71-83. [PubMed:11438309]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Resolor (prucalopride) EMA label [Link]

Drug created on March 19, 2008 10:34 / Updated on February 17, 2019 16:46