SAFINAMIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H19FN2O2
Molecular Weight	302.3434
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

C[C@H](NCC1=CC=C(OCC2=CC(F)=CC=C2)C=C1)C(N)=O

InChI

InChIKey=NEMGRZFTLSKBAP-LBPRGKRZSA-N

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

HIDE SMILES / InChI

Molecular Formula	C17H19FN2O2
Molecular Weight	302.3434
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Safinamide (FCE 26743, NW 1015, PNU 151774, PNU 151774E, trade name Xadago) combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide is under development with Newron, Zambon and Meiji Seika Pharma for the treatment of Parkinson's disease. Safinamide has been launched in the EU, Iceland and Liechtenstein. Safinamide was well tolerated and safe in the clinical development program that demonstrated the amelioration of motor symptoms and OFF phenomena by safinamide when combined with dopamine agonists or levodopa.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Monoamine oxidase B 72	Inhibitor 8,297	98.0 nM [IC50]
Sodium channel alpha subunit 76	Blocker 537	8.0 µM [IC50]
glutamate secretion 3	Inhibitor 8,297	56.4 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Parkinson's disease 226	Primary		Approved 8,429	XADAGO

C_max

Value	Dose	Co-administered	Analyte	Population
650 ng/mL	100 mg single, oral		SAFINAMIDE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
19000 ng × h/mL	100 mg single, oral		SAFINAMIDE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
26 h	single, intravenous		SAFINAMIDE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
11.5%	100 mg single, oral		SAFINAMIDE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 1 times / day single, oral Highest studied dose	healthy, mean age 28.7 years	Other AEs: Headache...
350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years	Other AEs: Diarrhea, Headache...
350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years	Disc. AE: ALT increased... Other AEs: Palpitations, Nausea...
350 mg 1 times / day multiple, oral Higher than recommended	healthy	Other AEs: Headache, Dizziness...
100 mg 1 times / day multiple, oral Recommended	unhealthy	Disc. AE: Angina pectoris, Aortic valve incompetence...

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AEs

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AE	Significance	Dose	Population
Headache	grade 1, 16.7%	400 mg 1 times / day single, oral Highest studied dose	healthy, mean age 28.7 years
Diarrhea	5.5%	350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years
Headache	5.5%	350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years
Headache	5.5%	350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years
Nausea	5.5%	350 mg 1 times / day multiple, oral Higher than recommended	healthy, mean age 41.2 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT2 647 OATP1B1 788 OATP1B3 706 BSEP 402 BCRP 699 P-gp 1,461 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A4/5 278 CYP1A1 110 CYP1A2 1,524 ALDH1 40	ALDH 6 P-gp 1,537 UGT1A 7	CYP1A2 701 CYP2B6 547 UGT1A1 69 SULT2A1 4

Drug as perpetrator

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Target	Modality	Activity	Metabolite
BCRP 773	inhibitor 3,277	no [IC50 43 uM]
BSEP 403	inhibitor 3,277	no
CYP1A2 1,692	inhibitor 3,277	no	NW-1153 3
CYP1A2 1,692	inhibitor 3,277	no	NW-1689 3
CYP2A6 739	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity
CYP3A4 1,737	substrate 3,367	minor
P-gp 1,537	substrate 3,367	no
ALDH 6	substrate 3,367	yes
UGT1A 7	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA0038VE	https://www.aablocks.com/goods/Goods/detail?id=AA0038VE
Aaron Chemicals	AR0039N6	http://www.aaronchem.com/133865-89-1
abcr GmbH	AB506034	http://www.abcr.com/shop/en/AB506034
Aceschem	ACF023692	https://www.aceschem.com/catalog/133865-89-1.html
Achemo Scientific Limited	AC-74101	http://www.achemo.com/search/?Keyword= 133865-89-1

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PubMed

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Title	Date	PubMed
Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class.	2004 Mar 25	15027868
Safinamide.	2007 Jan	17199024
Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase.	2007 Oct 4	17824599

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Patents

Sample Use Guides

In Vivo Use Guide

Treatment with Xadago (Safinamide) should be started at 50 mg per day. This daily dose may be increased to 100 mg/day on the basis of individual clinical need.

Route of Administration: Oral

In Vitro Use Guide

Safinamide (PNU-151774E) reduces sustained repetitive firing in a use-dependent manner without modifying the first action potential in hippocampal cultured neurons. The inhibition of the currents by PNU-151774E was concentration-related from 10 to 200 μM.

Substance Class	Chemical
Record UNII	90ENL74SIG
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SAFINAMIDE

Official Name

English

EMD-1195686

Code

English

safinamide [INN]

Common Name

English

EMD 1195686

Code

English

SAFINAMIDE [MI]

Common Name

English

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Classification Tree

Code System

Code

Monoamine oxidase B inhibitors

WHO-ATC

N04BD03

Established Pharmacologic Class

NDF-RT

N0000175762

Enzyme Inhibitor

NCI_THESAURUS

C667

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Code System

Code

Type

Description

MESH

C092797

PRIMARY

LACTMED

Safinamide

PRIMARY

DAILYMED

90ENL74SIG

PRIMARY

CAS

133865-89-1

PRIMARY

DRUG BANK

DB06654

PRIMARY

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Related Record

Type

Details


					3OV8HVI592

AMINE OXIDASE (FLAVIN-CONTAINING) B

TARGET -> INHIBITOR

Comments:

Human liver mitochondrial fraction, 30-min pre-incubation with substance

Interaction Type:

REVERSIBLE

Qualification:

IC50

Amount:

52 NANOMOLAR (average)


					3OV8HVI592

AMINE OXIDASE (FLAVIN-CONTAINING) B

TARGET -> INHIBITOR

Interaction Type:

REVERSIBLE

Qualification:

IC50

Amount:


					3OV8HVI592

AMINE OXIDASE (FLAVIN-CONTAINING) B

TARGET -> INHIBITOR

Comments:

Human platelet rich plasma, 30-min pre-incubation with substance

Interaction Type:

REVERSIBLE

Qualification:

IC50

Amount:

9.3 NANOMOLAR (average)


					YS90V3DTX0

SAFINAMIDE MESYLATE

SALT/SOLVATE -> PARENT

Amount:


					B5QXZ49C7Y

AMINE OXIDASE (FLAVIN-CONTAINING) A

METABOLIC ENZYME -> SUBSTRATE

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Related Record

Type

Details


					WDP88GFK92

NW-1199

METABOLITE INACTIVE -> PARENT

Amount:


					P2678L357C

(S)-2-((4-((3-FLUOROBENZYL)OXY)BENZYL)AMINO)PROPIONIC ACID

METABOLITE INACTIVE -> PARENT


					C2GYP7EAW8

NW-1689 AG

METABOLITE INACTIVE -> PARENT


					24H4YYD325

NW-1717

METABOLITE -> PARENT


					9KQ2XQY9HW

NW-1689

METABOLITE INACTIVE -> PARENT

Amount:

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Related Record

Type

Details


					90ENL74SIG

SAFINAMIDE

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	[20 to 26] hours (average)

Volume of Distribution	PHARMACOKINETIC	165 LITERS (average)

Tmax	PHARMACOKINETIC	[1.8 to 2.8] hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator