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Fluticasone Furoate

HCID 9854489
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Basic informationOverviewNames & identifiersPropertiesSafety & regulationChemistry & industryRelated reactionsCompound notes
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Basic information

CAS
397864-44-7
Standard SMILES
C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)SCF
InChIKey
XTULMSXFIHGYFS-VLSRWLAYSA-N
Molecular formula
C27H29F3O6S
Average molar mass
538.6 g/mol
Monoisotopic mass
538.1636943

Overview

Fluticasone furoate is a trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl substituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. It has a role as an anti-asthmatic drug, a prodrug and an anti-allergic agent. It is an 11beta-hydroxy steroid, a steroid ester, a fluorinated steroid, a 2-furoate ester, a corticosteroid, a thioester and a 3-oxo-Delta(1),Delta(4)-steroid. It is functionally related to a fluticasone. It derives from a hydride of an androstane.

Names & identifiers

Preferred name
Fluticasone Furoate
IUPAC
[(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(fluoromethylsulfanylcarbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] furan-2-carboxylate
English name
FLUTICASONE FUROATE
Molecular formula
C27H29F3O6S
Molecular weight
538.58

Names & synonyms

Fluticasone furoate397864-44-7VeramystAllermistAvamysFuramistArnuity ElliptaEnnhaleFlonase SensimistGSK 685 698furoate de fluticasonefuroato de fluticasona
Show more names
Fluticasone Furoate-d3Gw 685698xUnii-js86977wnvFluticasone Foruatefluticasone fuorate
fluticasonum furoasGW685698XGSK 685698GW-685698XJS86977WNVGSK685968GSK-685968[(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(fluoromethylsulfanylcarbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] furan-2-carboxylate

Database identifiers

CAS
397864-44-7
PubChem CID
9854489
DTXSID
DTXSID401024827
ChEMBL
CHEMBL1676
ChEBI
CHEBI:74899
UNII
JS86977WNV

Properties

Computed structural properties

XLogP
4.8
Topological polar surface area
119 Ų
Hydrogen bond donors
1
Hydrogen bond acceptors
10
Rotatable bonds
6
Heavy atoms
37
Formal charge
0
Complexity
1,080

Experimental & physicochemical properties

Drugs · 2 items

Pharmaceuticals -> Dermatologicals -> Corticosteroids, dermatological preparations

Pharmaceuticals -> Listed in ZINC15

SolubilityInsoluble
Human Drugs · 4 items

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Endocrine DisruptorsPotential endocrine disrupting compound
Melting Point250-252

Physicochemical properties

Melting point
250 · 250-252°C (dec.)
Boiling point
625.2 · 625.2±55.0 °C(Predicted)
Density
1.39 · 1.39
storage temp.
-20 °C · -20°C Freezer
solubility
Chloroform (Slightly, Heated, Sonicated), Methanol (Slightly)

Safety & regulation

Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.

GHS classification

GHS Classification · 4 items

Danger

H360 (42.9%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 14 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard information

Hazard Classes and CategoriesRepr. 1B (42.9%)

Safety data

wgk
WGK 3
Signal word
Warning
Symbol(GHS)
GHS08
Storage Class
11 - Combustible Solids
Hazard statements
H361d
Hazard Classifications
Repr. 2
Precautionary statements
P201-P202-P280-P308+P313-P405-P501

Chemistry & industry

Pharmacology

ATC Code · 4 items

R - Respiratory system

R - Respiratory system

QR - Respiratory system

QR - Respiratory system

Protein BindingFluticasone furoate is >99% protein bound in serum and may be as high as 99.6%, predominantly to albumin (96%) and α1-acid glycoprotein (90%).
Pharmacodynamics · 1 item

Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man. Inhaled fluticasone furoate at repeat doses of up to 400 mcg in healthy subjects was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Reductions in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. For subjects with asthma, a randomized, double-blind, parallel-group trial in 104 pediatric subjects showed no difference between once-daily treatment with 50 mcg fluticasone compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC<sub>(0-24)</sub> following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 subjects with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC<sub>(0-24)</sub>, and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression. A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520).

Related reactions

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Compound notes

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On this pageBasic informationOverviewNames & identifiersPropertiesSafety & regulationChemistry & industryRelated reactionsCompound notes
EC Number
629-894-6
Nikkaji
J2.515.103H
pka
12.52 · 12.52±0.70(Predicted)
form
Solid
color
White to Off-White
InChIKey
XTULMSXFIHGYFS-XEVZMEAZNA-N
SMILES
[C@]12(C)C=CC(=O)C=C1[C@@H](F)C[C@@]1([H])[C@]3([H])C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)C4=CC=CO4)[C@@]3(C)C[C@H](O)[C@]21F |&1:0,8,11,13,16,18,32,35,37,r|
FDA UNII
86977 WNV · JS86977WNV
ATC code
1 AD12,R03BA09 · R01AD12,R03BA09
UNSPSC Code
12352200 · 12352200
NACRES
77 · NA.77
Symbol(GHS)
8 · GHS08
Signal word
Warning
Hazard statements
361 d · H361d
Precautionary statements
201 · P201-P202-P280-P308+P313-P405-P501
WGK Germany
3 · WGK 3
Storage Class
11 · 11 - Combustible Solids
Hazard Classifications
2 · Repr. 2
Mechanism of Action · 1 item

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy.

Biological Half-Life · 1 item

Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours following inhalation.

Metabolism/Metabolites · 1 item

Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Fluticasone furoate is also hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

FDA Pharmacological Classification · 2 items

FLUTICASONE FUROATE

Corticosteroid Hormone Receptor Agonists [MoA]; Corticosteroid [EPC]

Absorption, Distribution and Excretion · 4 items

Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation. Intranasal exposure of fluticasone furoate also results in patients swallowing a larger portion of the dose.

Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose, and that in urine was approximately 1% of the total dose.

Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration.

Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 with a total plasma clearance of 65.4 L/hr. A study of 24 healthy Caucasian males also showed a clearance of 71.8L/h following intravenous administration.

Applications · 4 items

DescriptionFluticasone furoate is a new corticosteroid derivative launched as a nasal spray for the treatment of seasonal and perennial allergic rhinitis in adults and in children aged ≥2 years. It is structurally closely related to the previously marketed intranasal corticosteroid fluticasone propionate (FP). Both of these steroids contain the unusual S-fluoromethyl carbothioate group, which confers high lipophilicity and hence enhanced binding and retention of the drug by the nasal tissue. Additionally, the carbothioate group rapidly undergoes first-pass metabolism by CYP3A4, thus minimizing systemic exposure of the parent drug. Fluticasone furoate is a potent ligand for the glucocorticoid receptor (GR), with a relative receptor affinity (RRA) of 2,989 with reference to dexamethasone RRA of 100. Following intranasal administration, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive firstpass metabolism in the liver and gut, resulting in negligible systemic exposure. Pharmacokinetic studies using oral solution dosing and intravenous dosing show that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. The most common adverse reactions (W1% incidence) included headache, epistatix, sinus and throat pain, nasal ulceration, back pain, pyrexia, and cough. Fluticasone furoate is chemically derived starting from a readily available corticosteroid, 6a,9a-difluoro-11b,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17b-carboxylic acid, by first converting the carboxylic acid group to the corresponding carbothioic acid via activation with carbonyl diimidazole followed by reaction with hydrogen sulfide gas. Subsequently, selective acylation of the 17a-hydroxyl group with 2-furoyl chloride and alkylation of the 17b-carbothioic acid group with bromofluoromethane under basic conditions provides fluticasone furoate.

DescriptionFluticasone furoate is a synthetic glucocorticoid. It is selective for the glucocorticoid receptor over the mineralocorticoid, progesterone, and androgen receptors in reporter assays (EC50s = 0.03, 23.4, 0.9, and >10,000 nM, respectively), as well as estrogen receptor α (ERα) and ERβ in scintillation proximity assays (EC50s = >10,000 nM for both). Fluticasone furoate reduces LPS-induced increases in TNF-α production in human peripheral blood mononuclear cells (PBMCs) with an EC50 value of 0.12 nM. It decreases S. aureus enterotoxin-induced increases in IFN-γ, IL-2, IL-5, IL-17, and TNF-α levels in patient-derived nasal polyp tissue when used at a concentration of 100 nM. Intrathecal administration of fluticasone furoate (30 μg/animal) reduces ovalbumin-induced increases in bronchoalveolar lavage fluid (BALF) eosinophil infiltration in a rat model of allergic inflammation. Formulations containing fluticasone furoate have been used in the treatment of seasonal allergies.

UsesFluticasone-d3 Furoate is an isotope labelled form of Fluticasone Furoate (F599510). Fluticasone Furoate is a synthetic corticosteroid derived from fluticasone for treatment of seasonal allergic rhinitis.

UsesIt is one of the newest

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武汉英诺医药科技有限公司+86-027-59232304 15387063101 · [email protected]
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Additional notes · 1 item

DefinitionChEBI: A trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl s bstituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease.