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Identification
NameIngenol Mebutate
Accession NumberDB05013
TypeSmall Molecule
GroupsApproved
Description

Ingenol mebutate was approved by the FDA in January 2012, and it is marketed under the name Picato®. Picato gel is indicated for the topical treatment of actinic keratosis. Before approval, ingenol mebutate was called PEP005 as an investigational drug. PEP005 is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. PEP005 also has potent anti-leukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary AML cells at nanomolar concentrations.

Structure
Thumb
Synonyms
SynonymLanguageCode
3-Ingenyl AngelateNot AvailableNot Available
Ingenol 3-angelateNot AvailableNot Available
ingenol mebutateNot AvailableNot Available
PEP005Not AvailableNot Available
PicatoNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Picatogel150 ug/gtopicalLEO Pharma Inc.2012-01-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Picatogel500 ug/gtopicalLEO Pharma Inc.2012-01-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Picatogel0.015 %topicalLeo Pharma IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Picatogel0.05 %topicalLeo Pharma IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
Picato gel LEO Pharma
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number75567-37-2
WeightAverage: 430.5339
Monoisotopic: 430.23553882
Chemical FormulaC25H34O6
InChI KeyVDJHFHXMUKFKET-WDUFCVPESA-N
InChI
InChI=1S/C25H34O6/c1-7-12(2)22(29)31-21-13(3)10-24-14(4)8-17-18(23(17,5)6)16(20(24)28)9-15(11-26)19(27)25(21,24)30/h7,9-10,14,16-19,21,26-27,30H,8,11H2,1-6H3/b12-7-/t14-,16+,17-,18+,19-,21+,24+,25+/m1/s1
IUPAC Name
(1S,4S,5S,6R,9S,10R,12R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxotetracyclo[7.5.1.0¹,⁵.0¹⁰,¹²]pentadeca-2,7-dien-4-yl (2Z)-2-methylbut-2-enoate
SMILES
OCC1=C[C@]2([H])C(=O)[C@]3(C=C(C)[C@H](OC(=O)C(\C)=C/C)[C@@]3(O)[C@@H]1O)[C@H](C)C[C@@]1([H])C(C)(C)[C@@]21[H]
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acid esters
Direct ParentFatty acid esters
Alternative Parents
Substituents
  • Fatty acid ester
  • Alpha,beta-unsaturated carboxylic ester
  • Enoate ester
  • Tertiary alcohol
  • Secondary alcohol
  • Ketone
  • Carboxylic acid ester
  • 1,2-diol
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the topical treatment of actinic keratosis.
PharmacodynamicsThe pharmacodynamics of ingenol mebutate in producing cell death in actinic keratosis is unknown.
Mechanism of actionThe exact mechanism of action of ingenol mebutate in actinic keratosis is unknown. It is presumed to involve primary necrosis then neutrophil-mediated inflammation and antibody-dependent cell death of residual disease cells. Additionally in early studies, PEP005 was shown to be an effective activator of PKC-delta and PKC-delta translocation into nucleus and membranes. PEP005 also downregulates the expression and activity of PKC-alpha. PEP005 induced modulation of PKCs leads to Ras/Raf/MAPK and p38 activation and AKT/PKB inhibition.
AbsorptionSince ingenol mebutate is a topical treatment, the systemic absorption is less than 0.1 ng/mL.
Volume of distribution

There is no volume of distribution quantity since ingenol mebutate is a topical treatment.

Protein bindingThere is no plasma protein binding quantity since ingenol mebutate is a topical treatment
Metabolism

There is no metabolism of Picato since ingenol mebutate is a topical treatment, and ingenol mebutate does not inhibit or induce a majority of the cytochrome P450 (CYP) enzymes.

Route of eliminationThere is no route of elimination since ingenol mebutate is a topical treatment.
Half lifeThere is no half-life quantity since ingenol mebutate is a topical treatment.
Clearance

There is no clearance quantity since ingenol mebutate is a topical treatment.

ToxicityThe most common adverse reactions are local skin reactions at the application site, headache, periorbital edema,and nasopharyngitis.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8185
Blood Brain Barrier+0.5912
Caco-2 permeable-0.7076
P-glycoprotein substrateSubstrate0.7633
P-glycoprotein inhibitor INon-inhibitor0.7201
P-glycoprotein inhibitor IINon-inhibitor0.8873
Renal organic cation transporterNon-inhibitor0.9158
CYP450 2C9 substrateNon-substrate0.8455
CYP450 2D6 substrateNon-substrate0.8671
CYP450 3A4 substrateSubstrate0.6695
CYP450 1A2 substrateNon-inhibitor0.6961
CYP450 2C9 substrateNon-inhibitor0.5257
CYP450 2D6 substrateNon-inhibitor0.9137
CYP450 2C19 substrateNon-inhibitor0.817
CYP450 3A4 substrateNon-inhibitor0.8095
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8368
Ames testAMES toxic0.5474
CarcinogenicityNon-carcinogens0.9194
BiodegradationNot ready biodegradable0.7966
Rat acute toxicity2.7836 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9974
hERG inhibition (predictor II)Non-inhibitor0.844
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Geltopical0.015 %
Geltopical0.05 %
Geltopical150 ug/g
Geltopical500 ug/g
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada2301082 2009-02-032018-08-19
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.279 mg/mLALOGPS
logP2.49ALOGPS
logP2.51ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)12.09ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area104.06 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity117.86 m3·mol-1ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine D, Johns J, Scott TM, Sutherland KP, Gardner JM, Le TT, Lenarczyk A, Aylward JH, Parsons PG: Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004 Apr 15;64(8):2833-9.

General ReferenceNot Available
External Links
ATC CodesD06BX02
AHFS Codes
  • 84:92
PDB EntriesNot Available
FDA labelDownload (276 KB)
MSDSDownload (24.9 KB)
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

Targets

1. Protein kinase C delta type

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: ligand

Components

Name UniProt ID Details
Protein kinase C delta type Q05655 Details

References:

  1. Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM: Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004 May 1;64(9):3243-55. Pubmed

2. Protein kinase C alpha type

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: ligand

Components

Name UniProt ID Details
Protein kinase C alpha type P17252 Details

References:

  1. Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM: Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004 May 1;64(9):3243-55. Pubmed

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Drug created on October 21, 2007 16:23 / Updated on September 16, 2013 17:26