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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
SaltsNot Available
Brand names
NameCompany
PicatoNot Available
Picato gel LEO Pharma
Brand mixturesNot 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[7.5.1.0^{1,5}.0^{10,12}]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]
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassPrenol Lipids
SubclassDiterpenes
Direct parentDiterpenes
Alternative parentsTropones; Tertiary Alcohols; Enones; Carboxylic Acid Esters; Secondary Alcohols; 1,2-Diols; Ethers; Enolates; Primary Alcohols; Polyamines
Substituentstropone; tertiary alcohol; enone; 1,2-diol; carboxylic acid ester; secondary alcohol; ketone; primary alcohol; polyamine; ether; carboxylic acid derivative; enolate; alcohol; carbonyl group
Classification descriptionThis compound belongs to the diterpenes. These are terpene compounds formed by four isoprene units.
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
Property Value Probability
Human Intestinal Absorption + 0.8185
Blood Brain Barrier + 0.5912
Caco-2 permeable - 0.7076
P-glycoprotein substrate Substrate 0.7633
P-glycoprotein inhibitor I Non-inhibitor 0.7201
P-glycoprotein inhibitor II Non-inhibitor 0.8873
Renal organic cation transporter Non-inhibitor 0.9158
CYP450 2C9 substrate Non-substrate 0.8455
CYP450 2D6 substrate Non-substrate 0.8671
CYP450 3A4 substrate Substrate 0.6695
CYP450 1A2 substrate Non-inhibitor 0.6961
CYP450 2C9 substrate Non-inhibitor 0.5257
CYP450 2D6 substrate Non-inhibitor 0.9137
CYP450 2C19 substrate Non-inhibitor 0.817
CYP450 3A4 substrate Non-inhibitor 0.8095
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8368
Ames test AMES toxic 0.5474
Carcinogenicity Non-carcinogens 0.9194
Biodegradation Not ready biodegradable 0.7966
Rat acute toxicity 2.7836 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9974
hERG inhibition (predictor II) Non-inhibitor 0.844
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
GelTopical0.015%
GelTopical0.05%
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada2301082 2009-02-032018-08-19
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.279ALOGPS
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
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
ResourceLink
KEGG DrugD09393
PubChem Compound6918670
PubChem Substance12015710
ChemSpider5293863
ChEBI66913
ChEMBLCHEMBL1863513
RxListhttp://www.rxlist.com/picato-drug.htm
Drugs.comhttp://www.drugs.com/ppa/ingenol-mebutate.html
WikipediaIngenol_mebutate
ATC CodesD06BX02
AHFS Codes
  • 84:92
PDB EntriesNot Available
FDA labelshow(276 KB)
MSDSshow(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

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