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
38C836J57Z
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.

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 type B receptor subunit 1
agonist
Human
AGamma-aminobutyric acid receptor subunit alpha-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
AmikacinThe risk or severity of adverse effects can be increased when Progabide is combined with Amikacin.Approved, Investigational, Vet Approved
BenzphetamineThe risk or severity of adverse effects can be increased when Progabide is combined with Benzphetamine.Approved, Illicit
Benzyl alcoholThe risk or severity of adverse effects can be increased when Benzyl alcohol is combined with Progabide.Approved
BrompheniramineThe risk or severity of adverse effects can be increased when Brompheniramine is combined with Progabide.Approved
BupropionThe risk or severity of adverse effects can be increased when Bupropion is combined with Progabide.Approved
CaffeineProgabide may increase the excretion rate of Caffeine which could result in a lower serum level and potentially a reduction in efficacy.Approved
CarbamazepineThe risk or severity of adverse effects can be increased when Carbamazepine is combined with Progabide.Approved, Investigational
CetirizineThe risk or severity of adverse effects can be increased when Cetirizine is combined with Progabide.Approved
ChlorphenamineThe risk or severity of adverse effects can be increased when Chlorphenamine is combined with Progabide.Approved
ClemastineThe risk or severity of adverse effects can be increased when Clemastine is combined with Progabide.Approved, Investigational
ClindamycinThe risk or severity of adverse effects can be increased when Progabide is combined with Clindamycin.Approved, Vet Approved
CodeineThe risk or severity of adverse effects can be increased when Codeine is combined with Progabide.Approved, Illicit
CyclobenzaprineThe risk or severity of adverse effects can be increased when Cyclobenzaprine is combined with Progabide.Approved
CyclosporineThe risk or severity of adverse effects can be increased when Progabide is combined with Cyclosporine.Approved, Investigational, Vet Approved
DesvenlafaxineThe risk or severity of adverse effects can be increased when Progabide is combined with Desvenlafaxine.Approved, Investigational
DexbrompheniramineThe risk or severity of adverse effects can be increased when Dexbrompheniramine is combined with Progabide.Approved
DimenhydrinateThe risk or severity of adverse effects can be increased when Dimenhydrinate is combined with Progabide.Approved
DiphenhydramineThe risk or severity of adverse effects can be increased when Diphenhydramine is combined with Progabide.Approved, Investigational
DotarizineThe risk or severity of adverse effects can be increased when Progabide is combined with Dotarizine.Investigational
DoxofyllineThe serum concentration of Doxofylline can be decreased when it is combined with Progabide.Approved, Investigational
DoxylamineDoxylamine may increase the central nervous system depressant (CNS depressant) activities of Progabide.Approved, Vet Approved
EperisoneThe risk or severity of adverse effects can be increased when Progabide is combined with Eperisone.Approved, Investigational
EthanolProgabide may increase the central nervous system depressant (CNS depressant) activities of Ethanol.Approved
EthosuximideThe risk or severity of adverse effects can be increased when Ethosuximide is combined with Progabide.Approved
EtomidateThe risk or severity of adverse effects can be increased when Etomidate is combined with Progabide.Approved
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Progabide.Approved, Illicit, Investigational, Vet Approved
FlunarizineThe risk or severity of adverse effects can be increased when Flunarizine is combined with Progabide.Approved
FluoxetineThe risk or severity of adverse effects can be increased when Progabide is combined with Fluoxetine.Approved, Vet Approved
FluspirileneThe risk or severity of adverse effects can be increased when Fluspirilene is combined with Progabide.Approved, Investigational
Fluticasone propionateThe risk or severity of adverse effects can be increased when Fluticasone propionate is combined with Progabide.Approved
FluvoxamineThe risk or severity of adverse effects can be increased when Progabide is combined with Fluvoxamine.Approved, Investigational
GabapentinThe risk or severity of adverse effects can be increased when Gabapentin is combined with Progabide.Approved, Investigational
GanciclovirProgabide may increase the excretion rate of Ganciclovir which could result in a lower serum level and potentially a reduction in efficacy.Approved, Investigational
GuanfacineThe risk or severity of adverse effects can be increased when Guanfacine is combined with Progabide.Approved, Investigational
HydrocodoneProgabide may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.Approved, Illicit
HydroxyzineHydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Progabide.Approved
IsocarboxazidThe therapeutic efficacy of Progabide can be increased when used in combination with Isocarboxazid.Approved
LamotrigineThe risk or severity of adverse effects can be increased when Lamotrigine is combined with Progabide.Approved, Investigational
LevetiracetamThe risk or severity of adverse effects can be increased when Levetiracetam is combined with Progabide.Approved, Investigational
LevodopaThe risk or severity of adverse effects can be increased when Levodopa is combined with Progabide.Approved
LoratadineThe risk or severity of adverse effects can be increased when Loratadine is combined with Progabide.Approved, Investigational
Magnesium carbonateThe risk or severity of adverse effects can be increased when Progabide is combined with Magnesium carbonate.Approved, Investigational
Magnesium citrateThe risk or severity of adverse effects can be increased when Progabide is combined with Magnesium citrate.Approved
Magnesium hydroxideThe risk or severity of adverse effects can be increased when Progabide is combined with Magnesium hydroxide.Approved, Investigational
Magnesium sulfateThe therapeutic efficacy of Progabide can be increased when used in combination with Magnesium sulfate.Approved, Investigational, Vet Approved
Magnesium TrisilicateThe risk or severity of adverse effects can be increased when Progabide is combined with Magnesium Trisilicate.Approved
MeclizineThe risk or severity of adverse effects can be increased when Meclizine is combined with Progabide.Approved
MefloquineThe therapeutic efficacy of Progabide can be decreased when used in combination with Mefloquine.Approved, Investigational
MethsuximideThe risk or severity of adverse effects can be increased when Methsuximide is combined with Progabide.Approved
MianserinThe therapeutic efficacy of Progabide can be decreased when used in combination with Mianserin.Approved, Investigational
NeomycinThe risk or severity of adverse effects can be increased when Progabide is combined with Neomycin.Approved, Vet Approved
OndansetronThe risk or severity of adverse effects can be increased when Ondansetron is combined with Progabide.Approved
OrlistatThe serum concentration of Progabide can be decreased when it is combined with Orlistat.Approved, Investigational
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Progabide.Approved, Illicit, Investigational
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Progabide.Approved, Investigational, Vet Approved
ParomomycinThe risk or severity of adverse effects can be increased when Progabide is combined with Paromomycin.Approved, Investigational
ParoxetineThe risk or severity of adverse effects can be increased when Progabide is combined with Paroxetine.Approved, Investigational
PenfluridolThe risk or severity of adverse effects can be increased when Penfluridol is combined with Progabide.Experimental
PhenobarbitalThe risk or severity of adverse effects can be increased when Phenobarbital is combined with Progabide.Approved, Investigational
Polymyxin B SulfateThe risk or severity of adverse effects can be increased when Progabide is combined with Polymyxin B Sulfate.Approved, Vet Approved
PramipexoleProgabide may increase the sedative activities of Pramipexole.Approved, Investigational
PregabalinThe therapeutic efficacy of Progabide can be increased when used in combination with Pregabalin.Approved, Illicit, Investigational
ProchlorperazineThe risk or severity of adverse effects can be increased when Prochlorperazine is combined with Progabide.Approved, Vet Approved
PromethazineThe risk or severity of adverse effects can be increased when Promethazine is combined with Progabide.Approved, Investigational
PseudoephedrineThe risk or severity of adverse effects can be increased when Progabide is combined with Pseudoephedrine.Approved
PyrantelThe risk or severity of adverse effects can be increased when Progabide is combined with Pyrantel.Approved, Vet Approved
QuetiapineThe risk or severity of adverse effects can be increased when Quetiapine is combined with Progabide.Approved
RizatriptanThe risk or severity of adverse effects can be increased when Progabide is combined with Rizatriptan.Approved
RopiniroleProgabide may increase the sedative activities of Ropinirole.Approved, Investigational
ScopolamineThe risk or severity of adverse effects can be increased when Scopolamine is combined with Progabide.Approved, Investigational
SumatriptanThe risk or severity of adverse effects can be increased when Progabide is combined with Sumatriptan.Approved, Investigational
TetracyclineThe risk or severity of adverse effects can be increased when Progabide is combined with Tetracycline.Approved, Vet Approved
TetrahydropalmatineThe risk or severity of adverse effects can be increased when Tetrahydropalmatine is combined with Progabide.Investigational
TopiramateThe risk or severity of adverse effects can be increased when Topiramate is combined with Progabide.Approved
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Progabide.Approved, Investigational
TrimethadioneThe risk or severity of adverse effects can be increased when Progabide is combined with Trimethadione.Approved
ValaciclovirProgabide may increase the excretion rate of Valaciclovir which could result in a lower serum level and potentially a reduction in efficacy.Approved, Investigational
Valproic AcidThe risk or severity of adverse effects can be increased when Valproic Acid is combined with Progabide.Approved, Investigational
VancomycinThe risk or severity of adverse effects can be increased when Progabide is combined with Vancomycin.Approved
VecuroniumThe risk or severity of adverse effects can be increased when Progabide is combined with Vecuronium.Approved
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Progabide.Approved
VenlafaxineThe risk or severity of adverse effects can be increased when Progabide is combined with Venlafaxine.Approved
VinpocetineThe risk or severity of adverse effects can be increased when Progabide is combined with Vinpocetine.Investigational
ZiconotideThe risk or severity of adverse effects can be increased when Ziconotide is combined with Progabide.Approved
ZolmitriptanThe risk or severity of adverse effects can be increased when Progabide is combined with Zolmitriptan.Approved, Investigational
ZolpidemProgabide may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.Approved
ZonisamideThe risk or severity of adverse effects can be increased when Zonisamide is combined with Progabide.Approved, Investigational
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
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]
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]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 04:27