FINGOLIMOD

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H33NO2
Molecular Weight	307.4708
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1

InChI

InChIKey=KKGQTZUTZRNORY-UHFFFAOYSA-N

InChI=1S/C19H33NO2/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22/h9-12,21-22H,2-8,13-16,20H2,1H3

HIDE SMILES / InChI

Molecular Formula	C19H33NO2
Molecular Weight	307.4708
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Fingolimod (FTY720) is a sphingosine 1-phosphate receptor modulator indicated and approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod (trade name Gilenya, Novartis) is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Sphingosine 1-phosphate receptor Edg-1 12	Agonist 2,678	0.84 µM [IC50]
Sphingosine 1-phosphate receptor Edg-8 9	Agonist 2,678	2.1 µM [IC50]
Sphingosine 1-phosphate receptor Edg-6 9	Agonist 2,678	0.3 nM [EC50]
Sphingosine 1-phosphate receptor Edg-3 3	Agonist 2,678	0.3 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple sclerosis 104	Primary		Approved 8,429	GILENYA

C_max

Value	Dose	Co-administered	Analyte	Population
0.65 ng/mL	1 mg single, oral		FINGOLIMOD plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
149 ng × h/mL	1 mg single, oral		FINGOLIMOD plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
7 h	1 mg single, oral		FINGOLIMOD plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
14 mg single, oral Overdose	unhealthy, 33 years n = 1	Other AEs: Bradycardia, Hypotension...
1.25 mg 1 times / day steady, oral Highest studied dose	unhealthy, 36.0 years (range: 18–55 years) n = 46	Other AEs: Appendicitis, Urinary tract infection...
0.5 mg 1 times / day multiple, oral Recommended	unhealthy, 37 years n = 425	Disc. AE: Transaminases increased...
3.5 mg single, oral Highest studied dose	unhealthy, 43.2 years n = 3	Other AEs: Bradycardia, Carbon monoxide diffusing capacity decreased...
40 mg single, oral Overdose	unhealthy n = 6	Other AEs: Chest tightness...

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AEs

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AE	Significance	Dose	Population
Bradycardia	1 patient	14 mg single, oral Overdose	unhealthy, 33 years n = 1
Hypotension	1 patient	14 mg single, oral Overdose	unhealthy, 33 years n = 1
Hyperlipidemia	10.9%	1.25 mg 1 times / day steady, oral Highest studied dose	unhealthy, 36.0 years (range: 18–55 years) n = 46
Leukopenia	10.9%	1.25 mg 1 times / day steady, oral Highest studied dose	unhealthy, 36.0 years (range: 18–55 years) n = 46
Diarrhea	13%	1.25 mg 1 times / day steady, oral Highest studied dose	unhealthy, 36.0 years (range: 18–55 years) n = 46

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2C19 1,478 CYP2E1 882 CYP4A9/11 37 CYP2B6 810 CYP3A4/5 278 CYP2C8 911 BSEP 402 MRP2 383 P-gp 1,461 OATP1B1 788 OATP1B3 706 NTCP 34	CYP2E1 667 CYP1A1 349 CYP2J2 56 FMO3 67	CYP1A2 701 CYP2B6 547 CYP2C8 168 CYP2C19 293 P-gp 257

Drug as perpetrator

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Target	Modality	Activity	Metabolite
CYP1A2 1,692	inhibitor 3,277	no [IC50 >10 uM]	AML627 3
CYP1A2 1,692	inhibitor 3,277	no [IC50 >10 uM]	AML629 3
CYP2A6 739	inhibitor 3,277	no [IC50 >10 uM]	AML627 3
CYP2A6 739	inhibitor 3,277	no [IC50 >10 uM]	AML629 3
CYP2C19 1,553	inhibitor 3,277	no [IC50 >10 uM]	AML627 3

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	minor [Km 107 uM]	unlikely (co-administration study)
CYP2E1 667	substrate 3,367	minor [Km 73 uM]
FMO3 67	substrate 3,367	no
CYP1A1 349	substrate 3,367	yes [Km 117 uM]
CYP2J2 56	substrate 3,367	yes [Km 76 uM]

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626
hERG 1,647	inhibitor 1,626		FTY720-P 3

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63115	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63115
ChemicalBook	CB92498299	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92498299
MolPort	MolPort-003-847-513	https://www.molport.com/shop/molecule-link/MolPort-003-847-513
ZINC	ZINC000001542002	http://zinc15.docking.org/substances/ZINC000001542002
eMolecules	6843670	https://www.emolecules.com/cgi-bin/more?vid=6843670

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PubMed

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Title	Date	PubMed
Coexpression of CD4 and CD8alpha on rat T-cells in whole blood: a sensitive marker for monitoring T-cell immunosuppressive drugs.	2001 Aug 1	11406149
Proteasome inhibitors and immunosuppressive drugs promote the cleavage of eIF4GI and eIF4GII by caspase-8-independent mechanisms in Jurkat T cell lines.	2001 Aug 17	11513883
Combined FTY720/cyclosporine treatment promotes graft survival and lowers the peripheral lymphocyte count in a murine cardiac allotransplantation model.	2001 Jul 15	11468555
Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720.	2001 Jun	11429058
A high-capacity quantitative mouse model of drug-mediated immunosuppression based on rejection of an allogeneic subcutaneous tumor.	2001 Jun	11356940

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of GILENYA is 0.5 mg orally once-daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

Astrocytes derived from human fetal CNS specimens and maintained in dissociated cultures were exposed to 100 nM of the biologically active form of Fingolimod (FTY720) over a dosing regimen that ranged from a single exposure (with or without washout after 1 h) to daily exposures up to 5 days, a single addition of FTY720 inhibited subsequent S1PR ligand-induced pERK1/2 signaling for >24 h. Daily FTY720 treatments (3-5 days) maintained this effect together with a loss of proliferative responses to the natural ligand S1P. Repeated FTY720 dosing concurrently maintained a functional cell response as measured by the inhibition of intracellular calcium release when stimulated by the cytokine IL-1β. Recurrent FTY720 treatments did not inhibit serum- or IL-1β-induced pERK1/2.

Substance Class	Chemical
Record UNII	3QN8BYN5QF
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

FINGOLIMOD

Official Name

English

FTY-720

Code

English

FTY720

Code

English

FINGOLIMOD [MART.]

Common Name

English

FINGOLIMOD [MI]

Common Name

English

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Classification Tree

Code System

Code

Designated/Withdrawn

FDA ORPHAN DRUG

305910

Withdrawn

EU-Orphan Drug

EU/3/09/718

Multiple sclerosis

LIVERTOX

NBK548384

Selective immunosuppressants

WHO-VATC

QL04AA27

Established Pharmacologic Class

NDF-RT

N0000181816

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Code System

Code

Type

Description

WIKIPEDIA

FINGOLIMOD

PRIMARY

NCI_THESAURUS

C74202

PRIMARY

INN

8341

PRIMARY

EVMPD

SUB31908

PRIMARY

RXCUI

1012892

PRIMARY

RxNorm

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Related Record

Type

Details


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

99.7 % (average)


					J3HZQ9BE2S

FINGOLIMOD LAURYL SULFATE

SALT/SOLVATE -> PARENT

Amount:


					G926EC510T

FINGOLIMOD HYDROCHLORIDE

SALT/SOLVATE -> PARENT

Amount:


					3QN8BYN5QF

FINGOLIMOD

EXCRETED UNCHANGED

Comments:

After an oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-P are not excreted intact in urine but are the major components in the feces with amounts representing less than 2.5% of the dose each.

Qualification:

FECAL

Amount:

[<2.5] % (average)


					4PBV944KVV

CYTOCHROME P450 4F2

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR

Amount:

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Related Record

Type

Details


					S47P2YLH0U

DES(4-OCTYL) FINGOLIMOD-4-ACETIC ACID

METABOLITE -> PARENT

Amount:


					N6BC8JV9R2

FINGOLIMOD PALMITAMIDE

METABOLITE -> PARENT

Amount:


					O1T4NAT0IU

FINGOLIMOD OCTANOIC ACID

METABOLITE -> PARENT

Amount:


					CDR9R2KLH4

FINGOLIMOD HEXANOIC ACID

METABOLITE -> PARENT

Amount:


					92YDM6122J

FINGOLIMOD PHOSPHATE ESTER, (S)-

METABOLITE ACTIVE -> PRODRUG

Amount:

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Name	Property Type	Amount
Volume of Distribution	PHARMACOKINETIC	1200 LITERS [940 to 12260] (average)

Volume of Distribution	PHARMACOKINETIC	17.1 Liters/Kilogram (average)

Tmax	PHARMACOKINETIC	[12 to 16] hours (average)

Biological Half-life	PHARMACOKINETIC	[6 to 9] days (average)

Biological Half-life	PHARMACOKINETIC	[6 to 9] days (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator