Identification

Name
Progabide
Accession Number
DB00837  (APRD00072)
Type
Small Molecule
Groups
Approved, Investigational
Description

Progabide is an analog and prodrug of gamma-aminobutyric acid. It is commonly used in the treatment of epilepsy. It has agonistic activity for both the GABAA and GABAB receptors. Progabide has been investigated for many diseases besides epilepsy, including Parkinson's disease, schizophrenia, clinical depression and anxiety disorder with varying success.

Structure
Thumb
Synonyms
  • Halogabide
  • Progabida
  • Progabide
  • Progabidum
External IDs
SL 76 002 / SL-76002
International/Other Brands
Gabren / Gabrene (Sanofi S.A.)
Categories
UNII
112E50TORV
CAS number
62666-20-0
Weight
Average: 334.78
Monoisotopic: 334.0884336
Chemical Formula
C17H16ClFN2O2
InChI Key
IBALRBWGSVJPAP-FXBPSFAMSA-N
InChI
InChI=1S/C17H16ClFN2O2/c18-12-5-3-11(4-6-12)17(21-9-1-2-16(20)23)14-10-13(19)7-8-15(14)22/h3-8,10,22H,1-2,9H2,(H2,20,23)/b21-17-
IUPAC Name
4-[(Z)-[(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylidene]amino]butanimidic acid
SMILES
OC(=N)CCC\N=C(\C1=CC=C(Cl)C=C1)C1=C(O)C=CC(F)=C1

Pharmacology

Indication

Indicated for the treatment of epilepsy.

Structured Indications
Not Available
Pharmacodynamics

Progabide, a fatty acid derivative, is a GABA receptor agonist used to treat the symptoms of epilepsy.

Mechanism of action

Progabide binds to both GABAA and GABAB receptors located on the terminals of primary afferent fibers. Binding to GABAA results in an increased affinity of the GABA receptor for the amino acid, an augmented flux of chloride ions across the terminal membrane, and an increase in the amount of presynaptic inhibition. Activation of the GABAB receptors retards the influx of calcium ions into the terminals, thereby reducing the evoked release of excitatory amino acids and possibly other transmitters.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit alpha-1
agonist
Human
AGamma-aminobutyric acid type B receptor subunit 1
agonist
Human
Absorption

Well absorbed with a bioavailability of 60%

Volume of distribution
Not Available
Protein binding

95%

Metabolism

Hepatic

Route of elimination
Not Available
Half life

4 hours

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

Interactions

Drug Interactions
DrugInteractionDrug group
MefloquineThe therapeutic efficacy of Progabide can be decreased when used in combination with Mefloquine.Approved
MianserinThe therapeutic efficacy of Progabide can be decreased when used in combination with Mianserin.Approved, Investigational
OrlistatThe serum concentration of Progabide can be decreased when it is combined with Orlistat.Approved, Investigational
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Progabide.Approved
Food Interactions
Not Available

References

General References
  1. Bartholini G, Scatton B, Zivkovic B, Lloyd KG: GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease. Adv Neurol. 1987;45:79-83. [PubMed:3030072]
External Links
KEGG Drug
D05621
PubChem Compound
5361323
PubChem Substance
46506568
ChemSpider
10642379
ChEMBL
CHEMBL287631
Therapeutic Targets Database
DAP000258
PharmGKB
PA164747990
Wikipedia
Progabide
ATC Codes
N03AG05 — Progabide

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)133-135 °CPhysProp
water solubility70.9 mg/LNot Available
logP3.06FARRAJ,NF ET AL. (1988)
Predicted Properties
PropertyValueSource
Water Solubility0.00552 mg/mLALOGPS
logP3.22ALOGPS
logP1.47ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)-1.1ChemAxon
pKa (Strongest Basic)12ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area76.67 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity98.89 m3·mol-1ChemAxon
Polarizability33.53 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9959
Blood Brain Barrier+0.9534
Caco-2 permeable+0.5085
P-glycoprotein substrateSubstrate0.5433
P-glycoprotein inhibitor IInhibitor0.8381
P-glycoprotein inhibitor IINon-inhibitor0.9194
Renal organic cation transporterNon-inhibitor0.6
CYP450 2C9 substrateNon-substrate0.8307
CYP450 2D6 substrateNon-substrate0.7538
CYP450 3A4 substrateSubstrate0.5797
CYP450 1A2 substrateInhibitor0.507
CYP450 2C9 inhibitorNon-inhibitor0.5455
CYP450 2D6 inhibitorNon-inhibitor0.7138
CYP450 2C19 inhibitorInhibitor0.6943
CYP450 3A4 inhibitorInhibitor0.6492
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8101
Ames testNon AMES toxic0.567
CarcinogenicityNon-carcinogens0.8525
BiodegradationNot ready biodegradable0.9803
Rat acute toxicity2.4097 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8492
hERG inhibition (predictor II)Inhibitor0.5546
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
P-fluorophenols / Fluorobenzenes / Chlorobenzenes / 1-hydroxy-2-unsubstituted benzenoids / Aryl fluorides / Aryl chlorides / Secondary ketimines / Azomethines / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids
show 5 more
Substituents
Diphenylmethane / 4-fluorophenol / 4-halophenol / 1-hydroxy-2-unsubstituted benzenoid / Chlorobenzene / Fluorobenzene / Halobenzene / Phenol / Aryl chloride / Aryl fluoride
show 19 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
Molecular Weight
51801.395 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Agmo A, Belzung C: Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse. Pharmacol Biochem Behav. 1998 Jan;59(1):239-47. [PubMed:9443561]
  4. Grech DM, Balster RL: Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology (Berl). 1993;110(3):295-301. [PubMed:7831422]
  5. Fadda F, Mosca E, Meloni R, Gessa GL: Suppression by progabide of ethanol withdrawal syndrome in rats. Eur J Pharmacol. 1985 Mar 12;109(3):321-5. [PubMed:2985405]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR1
Uniprot ID
Q9UBS5
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 1
Molecular Weight
108319.4 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Agmo A, Belzung C: Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse. Pharmacol Biochem Behav. 1998 Jan;59(1):239-47. [PubMed:9443561]
  3. Fadda F, Mosca E, Meloni R, Gessa GL: Suppression by progabide of ethanol withdrawal syndrome in rats. Eur J Pharmacol. 1985 Mar 12;109(3):321-5. [PubMed:2985405]

Drug created on June 13, 2005 07:24 / Updated on December 01, 2017 14:35