Flupirtine

Identification

Name
Flupirtine
Accession Number
DB06623
Type
Small Molecule
Groups
Approved, Investigational
Description

Flupirtine is a pyridine derivative that is in clinical use as a nonopioid analgesic. It was approved for the treatment of pain in 1984 in Europe. It is not approved for use in the U.S. or Canada, but is currently in phase II trials for the treatment of fibromyalgia.

Structure
Thumb
Synonyms
  • Flupirtine
Product Ingredients
IngredientUNIICASInChI Key
Flupirtine gluconateD7NP6CR89M815586-85-7KTUKTXYTLNEYHO-IFWQJVLJSA-N
Flupirtine maleate0VCI53PK4A75507-68-5DPYIXBFZUMCMJM-BTJKTKAUSA-N
International/Other Brands
Awegal / Effirma / Efiret / Katadolon / Metanor / Trancolong
Categories
UNII
MOH3ET196H
CAS number
56995-20-1
Weight
Average: 304.3195
Monoisotopic: 304.133554013
Chemical Formula
C15H17FN4O2
InChI Key
JUUFBMODXQKSTD-UHFFFAOYSA-N
InChI
InChI=1S/C15H17FN4O2/c1-2-22-15(21)19-12-7-8-13(20-14(12)17)18-9-10-3-5-11(16)6-4-10/h3-8H,2,9H2,1H3,(H,19,21)(H3,17,18,20)
IUPAC Name
ethyl N-(2-amino-6-{[(4-fluorophenyl)methyl]amino}pyridin-3-yl)carbamate
SMILES
CCOC(=O)NC1=C(N)N=C(NCC2=CC=C(F)C=C2)C=C1

Pharmacology

Indication

Investigated for use/treatment in fibromyalgia.

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Flupirtine upregulates Bcl-2, increases glutathione levels, activates an inwardly rectifying potassium channel, and delays loss of intermitochondrial membrane calcium retention capacity. Flupirtine acts like a NMDA receptor antagonists, but does not bind to the receptor. One study concluded that the discriminative effects of flupirtine are neither of opioid nor of alpha-1 adrenergic type, but are primarily mediated through alpha-2 adrenergic mechanisms [PMID: 2901483].

TargetActionsOrganism
UAlpha-2A adrenergic receptorNot AvailableHuman
Absorption

Bioavailability: 90% (oral), 70% (rectal)

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound) and Para-fluorohippuric acid.

Route of elimination

72% of flupirtine and its metabolites appear in urine and 18% appear in faeces.

Half life

6.5 hrs (average), 11.2-16.8 hrs (average 14 hrs) (elderly), 8.7-10.9 hrs (average 9.8 hrs) (in those with moderate-level renal impairment).

Clearance
Not Available
Toxicity

Oral, mouse: LD50 = 300 mg/kg; Oral, rabbit: LD50 = 3200 mg/kg; Oral, rat: LD50 = 980 mg/kg.

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Muller WE, Laplanche JL, Ushijima H, Schroder HC: Novel approaches in diagnosis and therapy of Creutzfeldt-Jakob disease. Mech Ageing Dev. 2000 Jul 31;116(2-3):193-218. [PubMed:10996019]
  2. Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, Amalfitano A, Boustany RM: Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Ann Neurol. 2002 Apr;51(4):448-66. [PubMed:11921051]
  3. Swedberg MD, Shannon HE, Nickel B, Goldberg SR: Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat. J Pharmacol Exp Ther. 1988 Sep;246(3):1067-74. [PubMed:2901483]
  4. Abrams SM, Baker LR, Crome P, White AS, Johnston A, Ankier SI, Warrington SJ, Turner P, Niebch G: Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment. Postgrad Med J. 1988 May;64(751):361-3. [PubMed:3200777]
  5. Narang PK, Tourville JF, Chatterji DC, Gallelli JF: Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection. J Chromatogr. 1984 Jan 13;305(1):135-43. [PubMed:6707137]
External Links
KEGG Drug
D07978
PubChem Compound
53276
PubChem Substance
175427080
ChemSpider
48119
BindingDB
81199
ChEBI
94646
ChEMBL
CHEMBL255044
PharmGKB
PA166152829
Wikipedia
Flupirtine
ATC Codes
N02BG07 — Flupirtine
MSDS
Download (568 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableAxonal Change, Neuronal / Pain1
1CompletedBasic ScienceFlupirtine / Pain / Pharmacokinetics1
2TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1

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)115.5 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.0732 mg/mLALOGPS
logP2.61ALOGPS
logP2.67ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)12.9ChemAxon
pKa (Strongest Basic)7.5ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area89.27 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity85.49 m3·mol-1ChemAxon
Polarizability31.37 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9873
Blood Brain Barrier+0.9373
Caco-2 permeable-0.5757
P-glycoprotein substrateSubstrate0.5425
P-glycoprotein inhibitor INon-inhibitor0.8064
P-glycoprotein inhibitor IINon-inhibitor0.959
Renal organic cation transporterNon-inhibitor0.8922
CYP450 2C9 substrateNon-substrate0.8747
CYP450 2D6 substrateNon-substrate0.8227
CYP450 3A4 substrateNon-substrate0.6669
CYP450 1A2 substrateInhibitor0.7646
CYP450 2C9 inhibitorNon-inhibitor0.7681
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.5559
CYP450 3A4 inhibitorInhibitor0.7559
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5155
Ames testNon AMES toxic0.6798
CarcinogenicityNon-carcinogens0.8404
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5191 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9762
hERG inhibition (predictor II)Non-inhibitor0.5543
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 2-benzylaminopyridines. These are aromatic compounds containing pyridine ring substituted at the 2-position by a benzylamine group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzylamines
Direct Parent
2-benzylaminopyridines
Alternative Parents
Secondary alkylarylamines / Fluorobenzenes / Aminopyridines and derivatives / Imidolactams / Aryl fluorides / Heteroaromatic compounds / Carbamate esters / Organic carbonic acids and derivatives / Azacyclic compounds / Primary amines
show 5 more
Substituents
2-benzylaminopyridine / Aminopyridine / Fluorobenzene / Halobenzene / Secondary aliphatic/aromatic amine / Aryl fluoride / Aryl halide / Pyridine / Imidolactam / Heteroaromatic compound
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Swedberg MD, Shannon HE, Nickel B, Goldberg SR: Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat. J Pharmacol Exp Ther. 1988 Sep;246(3):1067-74. [PubMed:2901483]

Drug created on March 19, 2008 10:41 / Updated on December 01, 2017 17:35