Identification

Name
Ingenol Mebutate
Accession Number
DB05013
Type
Small Molecule
Groups
Approved
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
  • 3-Ingenyl Angelate
  • Ingenol 3-angelate
  • ingenol mebutate
External IDs
AGN 204332 / PEP-005 / PEP005
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PicatoGel0.015 %TopicalLeo Pharma2013-03-21Not applicableCanada
PicatoGel500 ug/gTopicalLeo Pharma2012-01-23Not applicableUs
PicatoGel150 micrograms/gCutaneousLeo Pharma2012-11-15Not applicableEu
PicatoGel150 ug/gTopicalLeo Pharma2012-01-23Not applicableUs
PicatoGel0.05 %TopicalLeo Pharma2013-03-21Not applicableCanada
PicatoGel500 micrograms/gCutaneousLeo Pharma2012-11-15Not applicableEu
International/Other Brands
Picato / Picato gel ( LEO Pharma)
Categories
UNII
7686S50JAH
CAS number
75567-37-2
Weight
Average: 430.5339
Monoisotopic: 430.23553882
Chemical Formula
C25H34O6
InChI Key
VDJHFHXMUKFKET-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

Pharmacology

Indication

For the topical treatment of actinic keratosis.

Structured Indications
Pharmacodynamics

The pharmacodynamics of ingenol mebutate in producing cell death in actinic keratosis is unknown.

Mechanism of action

The 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.

TargetActionsOrganism
UProtein kinase C delta type
ligand
Human
UProtein kinase C alpha type
ligand
Human
Absorption

Since 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 binding

There 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 elimination

There is no route of elimination since ingenol mebutate is a topical treatment.

Half life

There 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.

Toxicity

The most common adverse reactions are local skin reactions at the application site, headache, periorbital edema,and nasopharyngitis.

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

Interactions

Drug Interactions
No interactions found.
Food Interactions
  • No food effects found.

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 References
Not Available
External Links
KEGG Drug
D09393
PubChem Compound
6918670
PubChem Substance
175426930
ChemSpider
21171549
ChEBI
66913
ChEMBL
CHEMBL1863513
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ingenol_mebutate
ATC Codes
D06BX02 — Ingenol mebutate
AHFS Codes
  • 84:92.00 — Misc. Skin and Mucous Membrane Agents
FDA label
Download (276 KB)
MSDS
Download (24.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentMolluscum Contagiosum1
0WithdrawnTreatmentActinic Keratosis (AK)1
1CompletedNot AvailableActinic Keratosis (AK)3
1CompletedNot AvailableActinic Keratosis (AK) / Healthy Volunteers1
1CompletedDiagnosticHealthy Volunteers1
1CompletedTreatmentActinic Keratosis (AK)7
1RecruitingTreatmentVerruca Vulgaris1
1WithdrawnTreatmentWarts1
1, 2CompletedTreatmentActinic Keratosis (AK)2
2Active Not RecruitingTreatmentActinic Keratosis (AK)1
2CompletedTreatmentActinic Keratosis (AK)7
2CompletedTreatmentBasal Cell Carcinoma (BCC)2
2CompletedTreatmentExternal Genital Warts1
2CompletedTreatmentKeratosis1
2CompletedTreatmentKeratosis, Seborrheic1
2CompletedTreatmentPhoto-damage1
2CompletedTreatmentSquamous Cell Carcinoma (SCC)1
2CompletedTreatmentSuperficial Basal Cell Carcinoma2
2RecruitingTreatmentHutchinson's Melanotic Freckle1
3CompletedTreatmentActinic Keratosis (AK)13
4Active Not RecruitingTreatmentActinic Keratosis (AK)4
4CompletedTreatmentActinic Keratosis (AK)2
4RecruitingTreatmentActinic Keratosis (AK)1
Not AvailableActive Not RecruitingNot AvailableActinic Keratosis (AK)1
Not AvailableCompletedNot AvailableActinic Keratosis (AK)2
Not AvailableCompletedTreatmentActinic Keratosis (AK)1
Not AvailableUnknown StatusNot AvailableActinic Keratosis (AK)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GelCutaneous150 micrograms/g
GelCutaneous500 micrograms/g
GelTopical0.015 %
GelTopical0.05 %
GelTopical150 ug/g
GelTopical500 ug/g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2301082No2009-02-032018-08-19Canada
US7410656No1998-08-192018-08-19Us
US8536163No2006-12-182026-12-18Us
US8716271No2006-12-182026-12-18Us
US8735375No2006-12-182026-12-18Us
US6432452No1998-08-192018-08-19Us
US6787161No1998-08-192018-08-19Us
US6844013No1998-12-132018-12-13Us
US8278292No2007-07-062027-07-06Us
US8377919No2006-12-182026-12-18Us
US8372828No2006-12-182026-12-18Us
US8372827No2006-12-182026-12-18Us
US9789078No2013-05-152033-05-15Us

Properties

State
Solid
Experimental Properties
Not 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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.5257
CYP450 2D6 inhibitorNon-inhibitor0.9137
CYP450 2C19 inhibitorNon-inhibitor0.817
CYP450 3A4 inhibitorNon-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
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 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 tigliane and ingenane diterpenoids. These are diterpenoids containing the tigliane or ingenane carbon skeleton. The tigliane skeleton is a tetracyclic ring that consists of the 4/7/6/3 ring junction. It is derived from casbane by 6,10- and 5,14-cyclizations and is a framework of phorbol. The ingenane skeleton is derived by rearrangement of tigliane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Diterpenoids
Direct Parent
Tigliane and ingenane diterpenoids
Alternative Parents
Fatty acid esters / Tertiary alcohols / Enoate esters / Secondary alcohols / Ketones / Monocarboxylic acids and derivatives / Primary alcohols / Organic oxides / Hydrocarbon derivatives
Substituents
Ingenane diterpenoid / Fatty acid ester / Fatty acyl / Tertiary alcohol / Alpha,beta-unsaturated carboxylic ester / Enoate ester / Carboxylic acid ester / Ketone / Secondary alcohol / Monocarboxylic acid or derivatives
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Ligand
General Function
Protein serine/threonine kinase activity
Specific Function
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic ...
Gene Name
PRKCD
Uniprot ID
Q05655
Uniprot Name
Protein kinase C delta type
Molecular Weight
77504.445 Da
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:15126366]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Ligand
General Function
Zinc ion binding
Specific Function
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differenti...
Gene Name
PRKCA
Uniprot ID
P17252
Uniprot Name
Protein kinase C alpha type
Molecular Weight
76749.445 Da
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:15126366]

Drug created on October 21, 2007 16:23 / Updated on January 15, 2018 08:55