Identification

Name
Morniflumate
Accession Number
DB09285
Type
Small Molecule
Groups
Experimental
Description

Morniflumate is a non-steroidal anti-inflammatory drug with antipyretic properties. It is the morpholinoethyl ester of niflumic acid [8]. In one study, post morniflumate ingestion, physical examination and clinical symptoms of those with bronchitis showed improvement [1].

Structure
Thumb
Synonyms
  • Morniflumato
External IDs
UP 164
Categories
UNII
R133MWH7X1
CAS number
65847-85-0
Weight
Average: 395.382
Monoisotopic: 395.145676005
Chemical Formula
C19H20F3N3O3
InChI Key
LDXSPUSKBDTEKA-UHFFFAOYSA-N
InChI
InChI=1S/C19H20F3N3O3/c20-19(21,22)14-3-1-4-15(13-14)24-17-16(5-2-6-23-17)18(26)28-12-9-25-7-10-27-11-8-25/h1-6,13H,7-12H2,(H,23,24)
IUPAC Name
2-(morpholin-4-yl)ethyl 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylate
SMILES
FC(F)(F)C1=CC(NC2=C(C=CC=N2)C(=O)OCCN2CCOCC2)=CC=C1

Pharmacology

Indication

Morniflumate is indicated for the treatment of inflammatory conditions affecting the airways, ENT system, urogenital tract and bone and joint systems in adults. In Italy, morniflumate is also indicated for the treatment of pain associated with ear, nose, throat (ENT) and gastrointestinal inflammatory conditions in children. Morniflumate is a well established NSAID that has been in use for over three decades in Italy (particularly for the treatment of upper respiratory tract infections in children), France, Belgium, Austria, Switzerland, Spain and Portugal; it has a generally favorable tolerability profile.

Pharmacodynamics

Morniflumate, given at therapeutic dosages to healthy human volunteers, on leukotriene B4 (LTB4) and thromboxane (TXB2) synthesis, both in purified PMNs (polymorphnuclear neutrophils) and in whole blood [1].

In whole blood experiments, morniflumate reduced blood leukotriene B4 (LTB4) synthesis induced by Ca-ionophore A23187 Bx approximately 50%, both after a single dose and at steady state; the level of inhibition showed a pattern similar to the plasma levels of the bioactive metabolite of morniflumate (M1). The inhibition of serum thromboxane B2 (TXB2) levels was higher than 85%. Hence, morniflumate is demonstrated to reduce arachidonic acid metabolism, by exerting its effects on cyclooxygenase and 5-lipoxygenase. This characteristic might provide a better approach for anti-inflammatory therapy [A7899].

In several animal models orally administered morniflumate, the beta-morpholinoethyl ester of niflumic acid, proved almost equal to the parent compound in anti-inflammatory, analgesic and antipyretic activity with the absence of gastric irritating/ulcerogenic effects of its acidic parent compound [8].

Mechanism of action

The primary mechanism of niflumic acid and its ester is action is inhibition of enzymes involved in the synthesis of inflammatory prostaglandins [L14945]. This medication inhibits cyclooxygenase and 5-lipoxygenase pathways, which lead to fever and inflammation [11].

Niflumic acid, a calcium-activated Cl- channel blocker, is an analgesic and anti-inflammatory agent used in the treatment of inflammatory conditions. Niflumic acid does directly inhibit calcium channels or activate potassium channels. Niflumic acid selectively reduces noradrenaline- and 5-HT-induced pressor responses by inhibiting a mechanism which leads to the opening of voltage-gated calcium channels [11]. Niflumic acid (NFA) produces biphasic behavior on human CLC-K channels that suggests the presence of two functionally different binding sites: an activating site and a blocking site [11].

TargetActionsOrganism
UArachidonate 5-lipoxygenase
antagonist
Human
UProstaglandin G/H synthase 2Not AvailableHuman
ULeukotriene B4 receptor 1
antagonist
Human
UThromboxane A2 receptorNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

Strongly bound to plasma proteins with approximately 100% bioavailability [10].

Metabolism

The pharmacokinetic availability of niflumic acid in two different pharmaceutical preparations have been studied in 12 subjects after oral administration [10].

Bioavailability and pharmacokinetics studies after oral and intravenous (IV) administration demonstrate that morniflumate is absorbed as from the gastrointestinal tract, followed by rapid hydrolysis in the plasma, releasing the free acidic form, the molecule responsible for its anti-inflammatory effects. The ester displays gastroprotective effect against the ulcerogenic effects of niflumic acid [8].

Route of elimination

0.12 L /kg on average [10]

Half life

2h [10]

Clearance

45 ml/min [10]

Toxicity

As with other anti-inflammatory medications, adverse effects may include: agranulocytosis, bleeding, hepatotoxicity, acute renal failure, dermatoses, and rarely angioedema and urticaria [8].

Early supportive management in addition to careful monitoring of urine output and renal function is essential for patients with heart failure, chronic kidney and liver disease, and in patients taking a diuretic after major surgery while taking this medication [6].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when Morniflumate is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Morniflumate is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Morniflumate is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
4-hydroxycoumarinThe risk or severity of bleeding and hemorrhage can be increased when Morniflumate is combined with 4-hydroxycoumarin.
AbacavirMorniflumate may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Morniflumate is combined with Abciximab.
AcarboseMorniflumate may decrease the excretion rate of Acarbose which could result in a higher serum level.
AcebutololMorniflumate may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Morniflumate.
AcemetacinThe risk or severity of adverse effects can be increased when Acemetacin is combined with Morniflumate.
Food Interactions
Not Available

References

General References
  1. Melica A, Donateo L, Gerardi R, Parenti M: [A new anti-inflammatory-analgesic-antipyretic, morniflumate, in the treatment of chronic recurring bronchitis]. Riv Eur Sci Med Farmacol. 1991 Feb-Apr;13(1-2):51-60. [PubMed:1796197]
  2. Civelli M, Vigano T, Acerbi D, Caruso P, Giossi M, Bongrani S, Folco GC: Modulation of arachidonic acid metabolism by orally administered morniflumate in man. Agents Actions. 1991 Jul;33(3-4):233-9. [PubMed:1659152]
  3. Schiantarelli P, Cadel S, Acerbi D: A gastroprotective anti-inflammatory agent: the beta-morpholinoethyl ester of niflumic acid (morniflumate). Agents Actions. 1984 Feb;14(2):247-56. [PubMed:6608862]
  4. Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid. Biopharm Drug Dispos. 2006 Jan;27(1):1-6. [PubMed:16278927]
  5. Morniflumate [Link]
  6. Morniflumate [Link]
  7. Morniflumate induced urticaria and angioedema [Link]
  8. A gastroprotective anti-inflammatory agent: theβ-morpholinoethyl ester of niflumic acid (morniflumate) [Link]
  9. Modulation of arachidonic acid metabolism by orally administered morniflumate in man [Link]
  10. The pharmacokinetics and availability of niflumic acid in humans [Link]
  11. Niflumic acid [Link]
External Links
KEGG Drug
D05078
PubChem Compound
72106
PubChem Substance
310265178
ChemSpider
65089
ChEBI
136018
ChEMBL
CHEMBL2105059
Wikipedia
Morniflumate
ATC Codes
M01AX22 — Morniflumate

Clinical Trials

Clinical Trials
Not Available

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)75-77https://www.scbt.com/scbt/product/morniflumate-65847-85-0
water solubilitysoluble in DMSOhttps://www.medkoo.com/products/10883
Predicted Properties
PropertyValueSource
Water Solubility0.0861 mg/mLALOGPS
logP3.34ALOGPS
logP4.77ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)14.21ChemAxon
pKa (Strongest Basic)5.86ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.69 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity97.79 m3·mol-1ChemAxon
Polarizability38.37 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 trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Trifluoromethylbenzenes
Direct Parent
Trifluoromethylbenzenes
Alternative Parents
Pyridinecarboxylic acids / Aniline and substituted anilines / Aminopyridines and derivatives / Morpholines / Imidolactams / Vinylogous amides / Heteroaromatic compounds / Trialkylamines / Amino acids and derivatives / Carboxylic acid esters
show 10 more
Substituents
Trifluoromethylbenzene / Pyridine carboxylic acid / Pyridine carboxylic acid or derivatives / Aniline or substituted anilines / Aminopyridine / Morpholine / Oxazinane / Pyridine / Imidolactam / Heteroaromatic compound
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Iron ion binding
Specific Function
Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
Gene Name
ALOX5
Uniprot ID
P09917
Uniprot Name
Arachidonate 5-lipoxygenase
Molecular Weight
77982.595 Da
References
  1. A gastroprotective anti-inflammatory agent: theβ-morpholinoethyl ester of niflumic acid (morniflumate) [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Nucleotide binding
Specific Function
Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y r...
Gene Name
LTB4R
Uniprot ID
Q15722
Uniprot Name
Leukotriene B4 receptor 1
Molecular Weight
37556.925 Da
References
  1. Modulation of arachidonic acid metabolism by orally administered morniflumate in man [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Thromboxane a2 receptor activity
Specific Function
Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messen...
Gene Name
TBXA2R
Uniprot ID
P21731
Uniprot Name
Thromboxane A2 receptor
Molecular Weight
37430.69 Da
References
  1. Modulation of arachidonic acid metabolism by orally administered morniflumate in man [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Iron ion binding
Specific Function
Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
Gene Name
ALOX5
Uniprot ID
P09917
Uniprot Name
Arachidonate 5-lipoxygenase
Molecular Weight
77982.595 Da
References
  1. A gastroprotective anti-inflammatory agent: theβ-morpholinoethyl ester of niflumic acid (morniflumate) [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. A gastroprotective anti-inflammatory agent: theβ-morpholinoethyl ester of niflumic acid (morniflumate) [Link]
3. UDP-glucuronosyltransferase 1A9
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid. Biopharm Drug Dispos. 2006 Jan;27(1):1-6. [PubMed:16278927]

Drug created on October 29, 2015 12:08 / Updated on November 05, 2018 17:49