Identification

Name
Safinamide
Accession Number
DB06654
Type
Small Molecule
Groups
Approved
Description

Safinamide is for the treatment of parkinson's disease. It was approved in Europe in February 2015, and in the United States on March 21, 2017.

Structure
Thumb
Synonyms
Not Available
External IDs
EMD 1195686 / EMD-1195686
Product Ingredients
IngredientUNIICASInChI Key
Safinamide MesylateYS90V3DTX0202825-46-5YKOCHIUQOBQIAC-YDALLXLXSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XadagoTablet, film coated50 mg/1OralUs World Meds, Llc2017-05-08Not applicableUs
XadagoTablet, film coated100 mg/1OralUs World Meds, Llc2017-05-08Not applicableUs
Categories
UNII
90ENL74SIG
CAS number
133865-89-1
Weight
Average: 302.349
Monoisotopic: 302.143056023
Chemical Formula
C17H19FN2O2
InChI Key
NEMGRZFTLSKBAP-LBPRGKRZSA-N
InChI
InChI=1S/C17H19FN2O2/c1-12(17(19)21)20-10-13-5-7-16(8-6-13)22-11-14-3-2-4-15(18)9-14/h2-9,12,20H,10-11H2,1H3,(H2,19,21)/t12-/m0/s1
IUPAC Name
(2S)-2-[({4-[(3-fluorophenyl)methoxy]phenyl}methyl)amino]propanamide
SMILES
C[[email protected]](NCC1=CC=C(OCC2=CC(F)=CC=C2)C=C1)C(N)=O

Pharmacology

Indication

Safinamide is indicated as an add-on treatment to levodopa with or without other medicines for Parkinson’s disease

Structured Indications
Pharmacodynamics
Not Available
Mechanism of action

Safinamide is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model.

TargetActionsOrganism
AAmine oxidase [flavin-containing] B
antagonist
Human
Absorption

Rapid with peak plasma concentrations ranging from 2 to 4 h, total bioavailability is 95%. Food prolonged the rate and did not affect the extent of absorption of safinamide.

Volume of distribution

1.8 litres/kg

Protein binding

88–90%

Metabolism

The principal step is mediated by amidases which have not been identified, and produces safinamide acid. Other relevant metabolites are O-debenzylated safinamide, the N-dealkylated amine which is then oxidized to a carboxylic acid, and the glucuronide of the latter. In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies.

Route of elimination

76% renal, 1.5% faeces

Half life

22 h

Clearance

total oral clearance of plasma , which accounts for parent safinamide as well as metabolites, was on average only 17.53 ± 2.71 ml/h × kg

Toxicity

uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia) Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia.

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

Interactions

Drug Interactions
DrugInteractionDrug group
AmiodaroneThe metabolism of Safinamide can be decreased when combined with Amiodarone.Approved, Investigational
AprepitantThe serum concentration of Safinamide can be increased when it is combined with Aprepitant.Approved, Investigational
AtazanavirThe metabolism of Safinamide can be decreased when combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Safinamide can be decreased when combined with Atomoxetine.Approved
BoceprevirThe metabolism of Safinamide can be decreased when combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Safinamide can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Safinamide can be decreased when it is combined with Bosentan.Approved, Investigational
CarbamazepineThe metabolism of Safinamide can be increased when combined with Carbamazepine.Approved, Investigational
CeritinibThe serum concentration of Safinamide can be increased when it is combined with Ceritinib.Approved
ClarithromycinThe metabolism of Safinamide can be decreased when combined with Clarithromycin.Approved
ClemastineThe metabolism of Safinamide can be decreased when combined with Clemastine.Approved
ClotrimazoleThe metabolism of Safinamide can be decreased when combined with Clotrimazole.Approved, Vet Approved
CobicistatThe metabolism of Safinamide can be decreased when combined with Cobicistat.Approved
ConivaptanThe serum concentration of Safinamide can be increased when it is combined with Conivaptan.Approved, Investigational
CrizotinibThe metabolism of Safinamide can be decreased when combined with Crizotinib.Approved
CyclosporineThe metabolism of Safinamide can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Safinamide can be decreased when it is combined with Dabrafenib.Approved
DarunavirThe metabolism of Safinamide can be decreased when combined with Darunavir.Approved
DasatinibThe serum concentration of Safinamide can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Safinamide can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Safinamide can be decreased when combined with Delavirdine.Approved
DihydroergotamineThe metabolism of Safinamide can be decreased when combined with Dihydroergotamine.Approved
DiltiazemThe metabolism of Safinamide can be decreased when combined with Diltiazem.Approved
DoxycyclineThe metabolism of Safinamide can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Safinamide can be decreased when combined with Dronedarone.Approved
EltrombopagThe serum concentration of Safinamide can be increased when it is combined with Eltrombopag.Approved
EnzalutamideThe serum concentration of Safinamide can be decreased when it is combined with Enzalutamide.Approved
ErythromycinThe metabolism of Safinamide can be decreased when combined with Erythromycin.Approved, Vet Approved
FluconazoleThe metabolism of Safinamide can be decreased when combined with Fluconazole.Approved
FluvoxamineThe metabolism of Safinamide can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Safinamide can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Safinamide can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Safinamide can be increased when combined with Fosphenytoin.Approved
Fusidic AcidThe serum concentration of Safinamide can be increased when it is combined with Fusidic Acid.Approved
IdelalisibThe serum concentration of Safinamide can be increased when it is combined with Idelalisib.Approved
ImatinibThe metabolism of Safinamide can be decreased when combined with Imatinib.Approved
IndinavirThe metabolism of Safinamide can be decreased when combined with Indinavir.Approved
IsavuconazoniumThe metabolism of Safinamide can be decreased when combined with Isavuconazonium.Approved, Investigational
IsradipineThe metabolism of Safinamide can be decreased when combined with Isradipine.Approved
ItraconazoleThe metabolism of Safinamide can be decreased when combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Safinamide can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe metabolism of Safinamide can be decreased when combined with Ketoconazole.Approved, Investigational
LopinavirThe metabolism of Safinamide can be decreased when combined with Lopinavir.Approved
LovastatinThe metabolism of Safinamide can be decreased when combined with Lovastatin.Approved, Investigational
LuliconazoleThe serum concentration of Safinamide can be increased when it is combined with Luliconazole.Approved
LumacaftorThe metabolism of Safinamide can be increased when combined with Lumacaftor.Approved
MifepristoneThe serum concentration of Safinamide can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Safinamide can be decreased when it is combined with Mitotane.Approved
NefazodoneThe metabolism of Safinamide can be decreased when combined with Nefazodone.Approved, Withdrawn
NelfinavirThe metabolism of Safinamide can be decreased when combined with Nelfinavir.Approved
NetupitantThe serum concentration of Safinamide can be increased when it is combined with Netupitant.Approved
NevirapineThe metabolism of Safinamide can be increased when combined with Nevirapine.Approved
NilotinibThe metabolism of Safinamide can be decreased when combined with Nilotinib.Approved, Investigational
OlaparibThe metabolism of Safinamide can be decreased when combined with Olaparib.Approved
OsimertinibThe serum concentration of Safinamide can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Safinamide can be increased when it is combined with Palbociclib.Approved
PentobarbitalThe metabolism of Safinamide can be increased when combined with Pentobarbital.Approved, Vet Approved
PhenobarbitalThe metabolism of Safinamide can be increased when combined with Phenobarbital.Approved
PhenytoinThe metabolism of Safinamide can be increased when combined with Phenytoin.Approved, Vet Approved
PosaconazoleThe metabolism of Safinamide can be decreased when combined with Posaconazole.Approved, Investigational, Vet Approved
PrimidoneThe metabolism of Safinamide can be increased when combined with Primidone.Approved, Vet Approved
RanolazineThe metabolism of Safinamide can be decreased when combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Safinamide can be increased when combined with Rifabutin.Approved
RifampicinThe metabolism of Safinamide can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Safinamide can be increased when combined with Rifapentine.Approved
RitonavirThe metabolism of Safinamide can be decreased when combined with Ritonavir.Approved, Investigational
RolapitantThe serum concentration of Safinamide can be increased when it is combined with Rolapitant.Approved
SaquinavirThe metabolism of Safinamide can be decreased when combined with Saquinavir.Approved, Investigational
SildenafilThe metabolism of Safinamide can be decreased when combined with Sildenafil.Approved, Investigational
SiltuximabThe serum concentration of Safinamide can be decreased when it is combined with Siltuximab.Approved
SimeprevirThe serum concentration of Safinamide can be increased when it is combined with Simeprevir.Approved
St. John's WortThe serum concentration of Safinamide can be decreased when it is combined with St. John's Wort.Investigational, Nutraceutical
StiripentolThe serum concentration of Safinamide can be increased when it is combined with Stiripentol.Approved
SulfisoxazoleThe metabolism of Safinamide can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe metabolism of Safinamide can be decreased when combined with Telaprevir.Approved, Withdrawn
TelithromycinThe metabolism of Safinamide can be decreased when combined with Telithromycin.Approved
TeriflunomideThe serum concentration of Safinamide can be increased when it is combined with Teriflunomide.Approved
TiclopidineThe metabolism of Safinamide can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Safinamide can be decreased when it is combined with Tocilizumab.Approved
VenlafaxineThe metabolism of Safinamide can be decreased when combined with Venlafaxine.Approved
VerapamilThe metabolism of Safinamide can be decreased when combined with Verapamil.Approved
VoriconazoleThe metabolism of Safinamide can be decreased when combined with Voriconazole.Approved, Investigational
ZiprasidoneThe metabolism of Safinamide can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  1. Onofrj M, Bonanni L, Thomas A: An expert opinion on safinamide in Parkinson's disease. Expert Opin Investig Drugs. 2008 Jul;17(7):1115-25. doi: 10.1517/13543784.17.7.1115 . [PubMed:18549347]
  2. Stocchi F, Vacca L, Grassini P, De Pandis MF, Battaglia G, Cattaneo C, Fariello RG: Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition. Neurology. 2006 Oct 10;67(7 Suppl 2):S24-9. [PubMed:17030737]
  3. Marzo A, Dal Bo L, Monti NC, Crivelli F, Ismaili S, Caccia C, Cattaneo C, Fariello RG: Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol Res. 2004 Jul;50(1):77-85. [PubMed:15082032]
  4. Leuratti C, Sardina M, Ventura P, Assandri A, Muller M, Brunner M: Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-4):207-16. doi: 10.1159/000354805. Epub 2013 Oct 11. [PubMed:24136086]
  5. Schapira AH: Safinamide in the treatment of Parkinson's disease. Expert Opin Pharmacother. 2010 Sep;11(13):2261-8. doi: 10.1517/14656566.2010.511612. [PubMed:20707760]
External Links
PubChem Compound
131682
PubChem Substance
347827780
ChemSpider
116349
BindingDB
19187
ChEBI
134718
ChEMBL
CHEMBL396778

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
1CompletedTreatmentHealthy Volunteers1
1, 2CompletedNot AvailableIdiopathic Parkinson's Disease1
2CompletedSupportive CareParkinson's Disease (PD)1
2CompletedTreatmentParkinson's Disease With Cognitive Impairments1
2TerminatedBasic ScienceParkinson's Disease (PD)1
3CompletedTreatmentIdiopathic Parkinson's Disease2
3CompletedTreatmentParkinson's Disease (PD)4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8278485No2007-06-082027-06-08Us
US8283380No2007-09-012027-09-01Us
US8076515No2008-12-102028-12-10Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00989 mg/mLALOGPS
logP2.59ALOGPS
logP2.48ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)15.76ChemAxon
pKa (Strongest Basic)7.93ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area64.35 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity83 m3·mol-1ChemAxon
Polarizability32.16 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Alanine and derivatives / Benzylamines / Phenol ethers / Phenoxy compounds / Phenylmethylamines / Fluorobenzenes / Alkyl aryl ethers / Aralkylamines / Aryl fluorides / Primary carboxylic acid amides
show 6 more
Substituents
Alpha-amino acid amide / Alanine or derivatives / Phenoxy compound / Benzylamine / Phenol ether / Phenylmethylamine / Alkyl aryl ether / Fluorobenzene / Halobenzene / Aralkylamine
show 21 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Marzo A, Dal Bo L, Monti NC, Crivelli F, Ismaili S, Caccia C, Cattaneo C, Fariello RG: Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol Res. 2004 Jul;50(1):77-85. [PubMed:15082032]
  2. Authors unspecified: Safinamide: FCE 26743, NW 1015, PNU 151774, PNU 151774E. Drugs R D. 2004;5(6):355-8. [PubMed:15563241]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. Leonetti F, Capaldi C, Pisani L, Nicolotti O, Muncipinto G, Stefanachi A, Cellamare S, Caccia C, Carotti A: Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase. J Med Chem. 2007 Oct 4;50(20):4909-16. Epub 2007 Sep 7. [PubMed:17824599]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Leuratti C, Sardina M, Ventura P, Assandri A, Muller M, Brunner M: Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-4):207-16. doi: 10.1159/000354805. Epub 2013 Oct 11. [PubMed:24136086]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Leuratti C, Sardina M, Ventura P, Assandri A, Muller M, Brunner M: Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-4):207-16. doi: 10.1159/000354805. Epub 2013 Oct 11. [PubMed:24136086]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as estrone-3-sulfate (PubMed:10873595). Mediates transport of prostaglandins (PG) E1 and E2, thyroxine (T4), deltorphin II, BQ-123 an...
Gene Name
SLCO3A1
Uniprot ID
Q9UIG8
Uniprot Name
Solute carrier organic anion transporter family member 3A1
Molecular Weight
76552.135 Da
References
  1. Leuratti C, Sardina M, Ventura P, Assandri A, Muller M, Brunner M: Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-4):207-16. doi: 10.1159/000354805. Epub 2013 Oct 11. [PubMed:24136086]

Drug created on March 19, 2008 10:45 / Updated on November 09, 2017 03:54