Identification

Name
Tafluprost
Accession Number
DB08819
Type
Small Molecule
Groups
Approved
Description

A prostaglandin analogue ester prodrug used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. Chemically, tafluprost is a fluorinated analog of prostaglandin F2-alpha. Tafluprost was approved for use in the U.S. on February 10, 2012.

Structure
Thumb
Synonyms
  • AFP-168
External IDs
MK-2452
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SaflutanSolution4.5 mcgOphthalmicPurdue PharmaNot applicableNot applicableCanada
ZioptanSolution / drops0.0045 mg/0.3mLOphthalmicAkorn2014-11-26Not applicableUs
ZioptanSolution0.0045 mg/0.3mLOphthalmicMerck Sharp & Dohme Limited2012-02-102016-06-30Us
International/Other Brands
Taflotan (Regeneron Pharmaceuticals) / Zioptan
Categories
UNII
1O6WQ6T7G3
CAS number
209860-87-7
Weight
Average: 452.5313
Monoisotopic: 452.237430608
Chemical Formula
C25H34F2O5
InChI Key
WSNODXPBBALQOF-VEJSHDCNSA-N
InChI
InChI=1S/C25H34F2O5/c1-18(2)32-24(30)13-9-4-3-8-12-20-21(23(29)16-22(20)28)14-15-25(26,27)17-31-19-10-6-5-7-11-19/h3,5-8,10-11,14-15,18,20-23,28-29H,4,9,12-13,16-17H2,1-2H3/b8-3-,15-14+/t20-,21-,22+,23-/m1/s1
IUPAC Name
propan-2-yl (5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl]hept-5-enoate
SMILES
CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1

Pharmacology

Indication

Tafluprost is indicated for reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Associated Conditions
Pharmacodynamics

Tafluprost is a novel prostaglandin analog with a high affinity for the fluoroprostaglandin (FP) receptor PGF2α. Tafluprost has an affinity for the FP receptor that is approximately 12 times higher than that of the carboxylic acid of latanoprost, but with almost no potential to bind to other receptors.

Mechanism of action

Tafluprost acid is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and humans suggest that the main mechanism of action is increased uveoscleral outflow.

TargetActionsOrganism
AProstaglandin F2-alpha receptor
agonist
Human
Absorption

Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Tafluprost is an ester which makes the drug lipophillic enough to be quickly absorbed through. When administered to the eye, the peak plasma concentration (Cmax) and time to peak plasma concentration (Tmax) of tafluprost acid in healthy subjects was 26 pg/mL and 10 minutes respectively. a AUC, tafluprost acid = 394 pgmin/mL - 432 pgmin/mL.

Volume of distribution

The highest concentration of tafluprost acid was found in the cornea and conjunctiva.

Protein binding
Not Available
Metabolism

Tafluprost is an ester prodrug which is rapidly hydrolyzed by corneal esterases to form its biologically active acid metabolite. Tafluprost acid is further metabolized via fatty acid β-oxidation and phase II conjugation into 1,2,3,4-tetranor acid.

Route of elimination

Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution. In male rats, it was observed that tafluprost was excreted into the feces.

Half life
Not Available
Clearance
Not Available
Toxicity

Most common ocular adverse reaction is conjunctival hyperemia (range 4% – 20%).

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe therapeutic efficacy of Tafluprost can be decreased when used in combination with (4R)-limonene.
AceclofenacThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Acetylsalicylic acid.
AlclofenacThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Alclofenac.
AlminoprofenThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Alminoprofen.
AndrographolideThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Andrographolide.
AnisodamineThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Anisodamine.
AntipyrineThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Antipyrine.
ApocyninThe therapeutic efficacy of Tafluprost can be decreased when used in combination with Apocynin.
Food Interactions
Not Available

References

General References
  1. Papadia M, Bagnis A, Scotto R, Traverso CE: Tafluprost for glaucoma. Expert Opin Pharmacother. 2011 Oct;12(15):2393-401. doi: 10.1517/14656566.2011.606810. [PubMed:21916788]
  2. Pantcheva MB, Seibold LK, Awadallah NS, Kahook MY: Tafluprost: a novel prostaglandin analog for treatment of glaucoma. Adv Ther. 2011 Sep;28(9):707-15. doi: 10.1007/s12325-011-0055-8. Epub 2011 Aug 18. [PubMed:21858491]
  3. Takagi Y, Nakajima T, Shimazaki A, Kageyama M, Matsugi T, Matsumura Y, Gabelt BT, Kaufman PL, Hara H: Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004 Apr;78(4):767-76. [PubMed:15037111]
  4. Fukano Y, Kawazu K: Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats. Drug Metab Dispos. 2009 Aug;37(8):1622-34. doi: 10.1124/dmd.108.024885. Epub 2009 May 28. [PubMed:19477946]
External Links
Human Metabolome Database
HMDB0015704
KEGG Drug
D06274
PubChem Compound
9868491
PubChem Substance
175427102
ChemSpider
8044182
ChEBI
66899
ChEMBL
CHEMBL1963683
PharmGKB
PA165958432
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Tafluprost
ATC Codes
S01EE05 — Tafluprost
AHFS Codes
  • 52:40.28 — Prostaglandin Analogs
FDA label
Download (274 KB)
MSDS
Download (22.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentGlaucoma / Ocular Hypertension1
1, 2CompletedTreatmentGlaucoma and Ocular Hypertension1
3CompletedTreatmentGlaucoma / Ocular Hypertension1
3CompletedTreatmentOcular Hypertension / Open Angle Glaucoma (OAG)1
3CompletedTreatmentOcular Hypertension / Open-angle Glaucoma (OAG)6
3Unknown StatusTreatmentGlaucoma1
4CompletedTreatmentGlaucoma1
4CompletedTreatmentGlaucoma, Primary Open Angle (POAG)1
4CompletedTreatmentGlaucoma, Primary Open Angle (POAG) / Ocular Hypertension2
4CompletedTreatmentGlaucoma / Ocular Hypertension1
4CompletedTreatmentGlaucoma / Ocular Surface Disease1
4CompletedTreatmentOcular Hypertension / Open-angle Glaucoma (OAG)2
4RecruitingTreatmentGlaucoma / Ocular Hypertension1
4WithdrawnPreventionGlaucoma / Ocular Hypertension / Thyroid Eye Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionOphthalmic4.5 mcg
SolutionOphthalmic0.0045 mg/0.3mL
Solution / dropsOphthalmic0.0045 mg/0.3mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5886035No1997-12-182017-12-18Us
US9999593No2009-05-282029-05-28Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)87.5 °CNot Available
boiling point (°C)100°C Not Available
water solubilityInsoluble FDA label
logP4.05Not Available
pKa5.5-6.7FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00528 mg/mLALOGPS
logP4.46ALOGPS
logP4.29ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)14.51ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area75.99 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity120.59 m3·mol-1ChemAxon
Polarizability48.65 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9644
Blood Brain Barrier+0.8687
Caco-2 permeable+0.5372
P-glycoprotein substrateSubstrate0.5871
P-glycoprotein inhibitor INon-inhibitor0.9015
P-glycoprotein inhibitor IINon-inhibitor0.7888
Renal organic cation transporterNon-inhibitor0.8711
CYP450 2C9 substrateNon-substrate0.8086
CYP450 2D6 substrateNon-substrate0.854
CYP450 3A4 substrateSubstrate0.6508
CYP450 1A2 substrateNon-inhibitor0.75
CYP450 2C9 inhibitorNon-inhibitor0.7344
CYP450 2D6 inhibitorNon-inhibitor0.9056
CYP450 2C19 inhibitorNon-inhibitor0.6873
CYP450 3A4 inhibitorNon-inhibitor0.8038
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7418
Ames testNon AMES toxic0.7286
CarcinogenicityNon-carcinogens0.9028
BiodegradationNot ready biodegradable0.9737
Rat acute toxicity3.7129 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9787
hERG inhibition (predictor II)Non-inhibitor0.7362
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Eicosanoids
Direct Parent
Prostaglandins and related compounds
Alternative Parents
Phenoxy compounds / Phenol ethers / Fatty acid esters / Alkyl aryl ethers / Cyclopentanols / Cyclic alcohols and derivatives / Carboxylic acid esters / Monocarboxylic acids and derivatives / Organofluorides / Organic oxides
show 3 more
Substituents
Prostaglandin skeleton / Phenoxy compound / Phenol ether / Alkyl aryl ether / Fatty acid ester / Benzenoid / Monocyclic benzene moiety / Cyclopentanol / Cyclic alcohol / Secondary alcohol
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
organofluorine compound, carboxylic ester, prostaglandins Falpha (CHEBI:66899)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Prostaglandin f receptor activity
Specific Function
Receptor for prostaglandin F2-alpha (PGF2-alpha). The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Initiates luteolysis...
Gene Name
PTGFR
Uniprot ID
P43088
Uniprot Name
Prostaglandin F2-alpha receptor
Molecular Weight
40054.1 Da
References
  1. Pantcheva MB, Seibold LK, Awadallah NS, Kahook MY: Tafluprost: a novel prostaglandin analog for treatment of glaucoma. Adv Ther. 2011 Sep;28(9):707-15. doi: 10.1007/s12325-011-0055-8. Epub 2011 Aug 18. [PubMed:21858491]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Roh YJ, Park YG, Kang S, Kim SY, Moon JI: Effects of AFP-172 on COX-2-induced angiogenic activities on human umbilical vein endothelial cells. Graefes Arch Clin Exp Ophthalmol. 2012 Dec;250(12):1765-75. doi: 10.1007/s00417-012-2125-2. Epub 2012 Aug 22. [PubMed:22910791]

Drug created on February 24, 2012 10:29 / Updated on October 16, 2018 08:40