Identification

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Name
Grapiprant
Accession Number
DB12836
Type
Small Molecule
Groups
Investigational, Vet approved
Description

Grapiprant, also known as AT-001 and CJ-023, is a drug from the piprant class. These molecules were derived from acylsulfonamide and are characterized to be a novel series of para-N-acylaminomethylbenzoic acid known to be prostaglandin receptor antagonists.7 This type of molecules is currently in development for veterinary patients.1 This class of drugs was defined in 2013 by the World Health Organization.11

Grapiprant has been approved in March 2016 by the FDA's Center for Veterinary Medicine as a non-cyclooxygenase inhibiting NSAID for veterinary use.5

Structure
Thumb
Synonyms
Not Available
External IDs
AAT-007 / CJ 023423 / CJ-023,423 / CJ-023423 / MR-10A7 / MR10A7 / RQ-00000007
Categories
UNII
J9F5ZPH7NB
CAS number
415903-37-6
Weight
Average: 491.61
Monoisotopic: 491.199110988
Chemical Formula
C26H29N5O3S
InChI Key
HZVLFTCYCLXTGV-UHFFFAOYSA-N
InChI
InChI=1S/C26H29N5O3S/c1-5-24-29-25-19(4)28-18(3)16-23(25)31(24)21-10-8-20(9-11-21)14-15-27-26(32)30-35(33,34)22-12-6-17(2)7-13-22/h6-13,16H,5,14-15H2,1-4H3,(H2,27,30,32)
IUPAC Name
3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-(4-methylbenzenesulfonyl)urea
SMILES
CCC1=NC2=C(C)N=C(C)C=C2N1C1=CC=C(CCNC(=O)NS(=O)(=O)C2=CC=C(C)C=C2)C=C1

Pharmacology

Indication

The effects of grapiprant have been investigated in the area of analgesia and anti-inflammation due to the effects that have been reported about this molecule.1

This molecule has been approved and widely accepted to be used in veterinary for pain reduction in arthritis.4 In humans, it has been researched to be used in the control of pain and inflammation associated with osteoarthritis.10,9

The effect of grapiprant can be explained through the function of prostaglandin E2 (PGE2) which is a key mediator of swelling redness and pain which are classic signs of inflammation. The effect of PGE2 results from its action through four receptor EP1, EP2, EP3 and EP4 from which the EP4 is the primary mediator of PGE2-driven inflammation.2

Pharmacodynamics

Preclinical studies have shown that grapiprant is very effective to reduce acute and chronic pain and inflammation. The effect of grapiprant seems to be dose-dependent and it is comparable to the effect of rofecoxib and piroxicam.3

The effects of grapiprant have been reported to be effective in the relief from arthritic pain in canine patients. 1

Mechanism of action

Grapiprant is an EP4 prostaglandin receptor antagonist and thus the activity of this drug is thought to be completely related to the selective blockade of this receptor.1 It binds to human and other mammals EP4 prostaglandin receptor with high affinity without interfering with other prostaglandin pathways which are important for a variety of physiological functions. The binding of grapiprant blocks PGE2 binding and hence its biological effect related to the signaling pain and inflammation cascade.4

Grapiprant has been accepted very greatly in veterinary as its mechanism of action is a targeted approach to pain management by not having any interaction with the production of prostanoids and thus, by not interacting with other prostaglandin receptor pathways.1

TargetActionsOrganism
AProstaglandin E2 receptor EP4 subtype
antagonist
Humans
Absorption

Studies in animals (horse) have shown the presence of a concentration >0.005 ng/ml in serum 72 hours after initial administration of a dose of 2 mg/kg. It is rapidly absorbed and the reported Cmax in this reports was 31.9 ng/ml in a Tmax of 1.5 hours and AUC of 2000 ng.hr/ml.5 In the case of bioavailability, grapiprant presents a mean bioavailability of 39%.6 The bioavailability, time for peak concentration and maximal concentration has been reported to be significantly reduced after food.[A49842]

Volume of distribution

The reported volume of distribution in animal studies (cats) was reported to be 918 ml/kg.6

Protein binding

The serum protein binding of grapiprant was of about 95%.12 The main protein that binds to grapiprant is albumin.13

Metabolism

In vitro studies with dog microsomes have reported the identification of four metabolites, an N-deamination metabolite which is the major metabolite in urine and feces, two hydroxylated metabolites and one N-oxidation metabolite.12

Route of elimination

Following an oral dose, the majority of the dose an within the first 72 hours.12 Studies in animals (horse) have shown the presence of a concentration >0.005 ng/ml in urine 96 hours after initial administration of a dose of 2 mg/kg.5 From the excreted dose, 55%, 15% and 19% of the administered dose is excreted in bile, urine, and feces respectively.12

Half life

The reported elimination half-life in animal studies (horse) is of 5.86 hours.5

Clearance

The reported clearance rate in animal studies (cats) was reported to be 173.2 ml/hr.kg.6

Toxicity

Safety studies have demonstrated an excellent safety profile and a wide safety margin.1 In animal studies, the results of the 2.5-12X overdose were observed as soft-formed or mucous feces, occasionally bloody and vomiting.13

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.
DrugInteraction
AbemaciclibThe serum concentration of Grapiprant can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Grapiprant can be increased when it is combined with Acebutolol.
AcetaminophenThe serum concentration of Grapiprant can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe serum concentration of Grapiprant can be increased when it is combined with Acetylsalicylic acid.
AfatinibThe serum concentration of Grapiprant can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Grapiprant can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Grapiprant can be increased when it is combined with Aldosterone.
AlectinibThe serum concentration of Grapiprant can be increased when it is combined with Alectinib.
AlfentanilThe serum concentration of Grapiprant can be increased when it is combined with Alfentanil.
AlitretinoinThe serum concentration of Grapiprant can be increased when it is combined with Alitretinoin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Kirkby Shaw K, Rausch-Derra LC, Rhodes L: Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Sci. 2015 Dec 21;2(1):3-9. doi: 10.1002/vms3.13. eCollection 2016 Feb. [PubMed:29067176]
  2. Woodward DF, Jones RL, Narumiya S: International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev. 2011 Sep;63(3):471-538. doi: 10.1124/pr.110.003517. Epub 2011 Jul 13. [PubMed:21752876]
  3. Nakao K, Murase A, Ohshiro H, Okumura T, Taniguchi K, Murata Y, Masuda M, Kato T, Okumura Y, Takada J: CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007 Aug;322(2):686-94. doi: 10.1124/jpet.107.122010. Epub 2007 May 10. [PubMed:17495127]
  4. Rausch-Derra L, Huebner M, Wofford J, Rhodes L: A Prospective, Randomized, Masked, Placebo-Controlled Multisite Clinical Study of Grapiprant, an EP4 Prostaglandin Receptor Antagonist (PRA), in Dogs with Osteoarthritis. J Vet Intern Med. 2016 May;30(3):756-63. doi: 10.1111/jvim.13948. Epub 2016 Apr 13. [PubMed:27075237]
  5. Knych HK, Seminoff K, McKemie DS: Detection and pharmacokinetics of grapiprant following oral administration to exercised Thoroughbred horses. Drug Test Anal. 2018 Mar 25. doi: 10.1002/dta.2378. [PubMed:29575649]
  6. Lebkowska-Wieruszewska B, De Vito V, Owen H, Poapholatep A, Giorgi M: Pharmacokinetics of grapiprant, a selective EP4 prostaglandin PGE2 receptor antagonist, after 2 mg/kg oral and i.v. administrations in cats. J Vet Pharmacol Ther. 2017 Dec;40(6):e11-e15. doi: 10.1111/jvp.12414. Epub 2017 Apr 29. [PubMed:28459136]
  7. Okumura Y, Yamagishi T, Nukui S, Nakao K: Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist. Bioorg Med Chem Lett. 2017 Mar 1;27(5):1186-1192. doi: 10.1016/j.bmcl.2017.01.067. Epub 2017 Jan 25. [PubMed:28169162]
  8. Lebkowska-Wieruszewska B, Barsotti G, Lisowski A, Gazzano A, Owen H, Giorgi M: Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs. N Z Vet J. 2017 Jan;65(1):19-23. doi: 10.1080/00480169.2016.1241727. Epub 2016 Oct 19. [PubMed:27691904]
  9. Nagahisa A, Okumura T: Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther. 2017 Jun;40(3):285-292. doi: 10.1111/jvp.12349. Epub 2016 Sep 6. [PubMed:27597397]
  10. Vito V, Saba A, Lee HK, Owen H, Poapolathep A, Giorgi M: Detection and quantification of the selective EP4 receptor antagonist CJ-023423 (grapiprant) in canine plasma by HPLC with spectrofluorimetric detection. J Pharm Biomed Anal. 2016 Jan 25;118:251-258. doi: 10.1016/j.jpba.2015.11.004. Epub 2015 Nov 7. [PubMed:26580822]
  11. WHO [Link]
  12. Galliprant (Grapiprant) FDA veterinary label [File]
  13. Galliprant (Grapiprant) EMA veterinary label [File]
External Links
PubChem Compound
11677589
PubChem Substance
347829001
ChemSpider
9852318
BindingDB
50107283
ChEMBL
CHEMBL3039498
MSDS
Download (171 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentOsteoarthritis (OA)1
1RecruitingTreatmentMicrosatellite Stable Colorectal Cancer1
1, 2RecruitingTreatmentNon-small Cell Lung Cancer Adenocarcinoma1
2WithdrawnTreatmentBreast Cancer / Lung Cancer Non-Small Cell Cancer (NSCLC) / Prostate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>136 ºC (Grapiprant hydrochloride)'MSDS'
water solubilityInsoluble'MSDS'
logP4.56'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.00595 mg/mLALOGPS
logP4.06ALOGPS
logP2.27ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)4.33ChemAxon
pKa (Strongest Basic)6.86ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area105.98 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity145.76 m3·mol-1ChemAxon
Polarizability53.82 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
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 phenylimidazoles. These are polycyclic aromatic compounds containing a benzene ring linked to an imidazole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Imidazoles
Direct Parent
Phenylimidazoles
Alternative Parents
Tosyl compounds / Benzenesulfonamides / Imidazo-[4,5-c]pyridines / Benzenesulfonyl compounds / Sulfonylureas / Methylpyridines / N-substituted imidazoles / Organosulfonic acids and derivatives / Heteroaromatic compounds / Aminosulfonyl compounds
show 4 more
Substituents
1-phenylimidazole / Benzenesulfonamide / Tosyl compound / Imidazopyridine / Benzenesulfonyl group / Imidazo-[4,5-c]pyridine / Methylpyridine / Sulfonylurea / Toluene / Monocyclic benzene moiety
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Prostaglandin e receptor activity
Specific Function
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role...
Gene Name
PTGER4
Uniprot ID
P35408
Uniprot Name
Prostaglandin E2 receptor EP4 subtype
Molecular Weight
53118.845 Da
References
  1. Kirkby Shaw K, Rausch-Derra LC, Rhodes L: Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Sci. 2015 Dec 21;2(1):3-9. doi: 10.1002/vms3.13. eCollection 2016 Feb. [PubMed:29067176]
  2. Woodward DF, Jones RL, Narumiya S: International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev. 2011 Sep;63(3):471-538. doi: 10.1124/pr.110.003517. Epub 2011 Jul 13. [PubMed:21752876]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
References
  1. Galliprant (Grapiprant) EMA veterinary label [File]

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. Galliprant (Grapiprant) FDA veterinary label [File]

Drug created on October 20, 2016 18:37 / Updated on November 02, 2019 03:03