Identification
NameSafinamide
Accession NumberDB06654
TypeSmall Molecule
GroupsApproved
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
SynonymsNot Available
External IDs EMD 1195686 / EMD-1195686
Product Ingredients
IngredientUNIICASInChI KeyDetails
Safinamide MesylateYS90V3DTX0 202825-46-5YKOCHIUQOBQIAC-YDALLXLXSA-NDetails
Approved 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
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII90ENL74SIG
CAS number133865-89-1
WeightAverage: 302.349
Monoisotopic: 302.143056023
Chemical FormulaC17H19FN2O2
InChI KeyNEMGRZFTLSKBAP-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 Not Available
PharmacodynamicsNot 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.

TargetKindPharmacological actionActionsOrganismUniProt ID
Amine oxidase [flavin-containing] BProteinyes
antagonist
HumanP27338 details
Related Articles
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
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
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
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral50 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8278485 No2007-06-082027-06-08Us
US8283380 No2007-09-012027-09-01Us
US8076515 No2008-12-102028-12-10Us
Properties
StateSolid
Experimental PropertiesNot 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 featuresNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MSNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentAlpha amino acid amides
Alternative ParentsAlanine and derivatives / Benzylamines / Phenol ethers / Phenoxy compounds / Phenylmethylamines / Fluorobenzenes / Alkyl aryl ethers / Aralkylamines / Aryl fluorides / Primary carboxylic acid amides
SubstituentsAlpha-amino acid amide / Alanine or derivatives / Phenoxy compound / Benzylamine / Phenol ether / Phenylmethylamine / Alkyl aryl ether / Fluorobenzene / Halobenzene / Aralkylamine
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot 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 tissues. MAOB preferentially degrades benzylamine and phenylethylamine.
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 tissues. MAOA preferentially oxidizes biogenic amines such as 5-hydroxytryptamine (5-HT), norepinephrine and epinephrine.
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
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 and vasopressin, but not DPDPE (a derivative of enkephalin lacking an N-terminal tyrosine residue), estrone-3-sulfate, taurocholate, digoxin nor DHEAS (PubMed:16971491).
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 September 01, 2017 11:29