Identification

Name
Safinamide
Accession Number
DB06654
Type
Small Molecule
Groups
Approved, Investigational
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
  • Safinamida
  • Safinamide
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/1OralCatalent Germany Schorndorf GmbH2017-05-082018-02-05Us
XadagoTablet, film coated100 mg/1OralUS WorldMeds, LLC2017-05-08Not applicableUs
XadagoTablet, film coated50 mg/1OralUS WorldMeds, LLC2017-05-08Not applicableUs
XadagoTablet, film coated100 mg/1OralCatalent Germany Schorndorf GmbH2017-05-082018-02-05Us
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[C@H](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

Associated Conditions
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
Humans
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
DrugInteraction
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when Safinamide is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Safinamide is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidSafinamide may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Safinamide.
2,4-thiazolidinedioneSafinamide may increase the hypoglycemic activities of 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamineSafinamide may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineSafinamide may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Safinamide.
4-Bromo-2,5-dimethoxyamphetamineSafinamide may increase the hypertensive activities of 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Safinamide.
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
Wikipedia
Safinamide
ATC Codes
N04BD03 — Safinamide

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
4RecruitingTreatmentParkinson's Disease (PD)1

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)
US8278485No2012-10-022027-06-08Us
US8283380No2012-10-092027-09-01Us
US8076515No2011-12-132028-12-10Us

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
Humans
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
Humans
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
Humans
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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d 24-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 oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
There is limited data currently available on this enzyme inhibition.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 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. Malek NM, Grosset DG: Investigational agents in the treatment of Parkinson's disease: focus on safinamide. J Exp Pharmacol. 2012 Aug 14;4:85-90. doi: 10.2147/JEP.S34343. eCollection 2012. [PubMed:27186120]
  3. Safinamide FDA label [File]
  4. Safinamide, Pharmacology Review, FDA [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
CYP2E1 was inhibited by safinamide metabolites NW-1153 and NW 1689 at >100mcM [FDA Label].
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
CYP3A5 was inhibited by safinamide metabolites NW-1153 and NW 1689 at >100mcM [FDA Label].
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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
Kind
Protein
Organism
Humans
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 December 16, 2018 06:53