Ingenol mebutate
Identification
- Summary
Ingenol mebutate is a topical agent used for the treatment of actinic keratosis.
- Generic Name
- Ingenol mebutate
- DrugBank Accession Number
- DB05013
- Background
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.
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 430.541
Monoisotopic: 430.235538815 - Chemical Formula
- C25H34O6
- Synonyms
- 3-Angeloylingenol
- 3-Ingenyl angelate
- Ingenol 3-angelate
- Ingenol mebutate
- Ingenol mebutato
- Ingenoli mebutas
- Mébutate d'ingénol
- Mebutato de ingenol
- External IDs
- AGN 204332
- PEP-005
- PEP005
Pharmacology
- Indication
For the topical treatment of actinic keratosis.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Actinic keratosis •••••••••••• - Contraindications & Blackbox Warnings
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- 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.
Target Actions Organism UProtein kinase C delta type ligandHumans UProtein kinase C alpha type ligandHumans - 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.
- Adverse Effects
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- Toxicity
The most common adverse reactions are local skin reactions at the application site, headache, periorbital edema,and nasopharyngitis.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.No interactions found.
- Food Interactions
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Picato gel ( LEO Pharma)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Picato Gel 500 ug/1g Topical LEO Pharma Inc. 2012-01-23 2022-04-30 US Picato Gel 150 micrograms/g Cutaneous Leo Laboratories Ltd. 2016-09-08 2020-07-31 EU Picato Gel 150 ug/1g Topical LEO Pharma Inc. 2012-01-23 2022-02-28 US Picato Gel 0.05 % Topical Leo Pharma 2013-03-21 2020-10-14 Canada Picato Gel 0.015 % Topical Leo Pharma 2013-03-21 2020-10-14 Canada
Categories
- ATC Codes
- D06BX02 — Ingenol mebutate
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Alcohol / Aliphatic homopolycyclic compound / Alpha,beta-unsaturated carboxylic ester / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Enoate ester / Fatty acid ester / Fatty acyl / Hydrocarbon derivative
- Molecular Framework
- Aliphatic homopolycyclic compounds
- External Descriptors
- carboxylic ester, tetracyclic diterpenoid, cyclic terpene ketone (CHEBI:66913)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 7686S50JAH
- CAS number
- 75567-37-2
- InChI Key
- VDJHFHXMUKFKET-UXMMOKKRSA-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,9R,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
- [H][C@@]12C[C@@H](C)[C@]34C=C(C)[C@H](OC(=O)C(\C)=C/C)[C@@]3(O)[C@H](O)C(CO)=C[C@@]([H])(C4=O)[C@]1([H])C2(C)C
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
- 28533061
- 1242806
- ChEBI
- 66913
- ChEMBL
- CHEMBL1863513
- ZINC
- ZINC000056898854
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ingenol_mebutate
- FDA label
- Download (276 KB)
- MSDS
- Download (24.9 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Actinic Keratosis (AK) 6 4 Unknown Status Treatment Actinic Keratosis (AK) 1 3 Completed Treatment Actinic Keratosis (AK) 13 3 Terminated Treatment Actinic Keratosis (AK) 1 2 Completed Treatment Actinic Keratosis (AK) 7
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Gel Cutaneous 150 micrograms/g Gel Cutaneous 150 MICROGRAMMI/G Gel Cutaneous 500 micrograms/g Gel Cutaneous 500 MICROGRAMMI/G Gel Topical 0.015 % Gel Topical 0.05 % Gel Topical 150 ug/1g Gel Topical 500 ug/1g - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region CA2301082 No 2009-02-03 2018-08-19 Canada US7410656 No 2008-08-12 2018-08-19 US US8536163 No 2013-09-17 2026-12-18 US US8716271 No 2014-05-06 2026-12-18 US US8735375 No 2014-05-27 2026-12-18 US US6432452 No 2002-08-13 2018-08-19 US US6787161 No 2004-09-07 2018-08-19 US US6844013 No 2005-01-18 2018-12-13 US US8278292 No 2012-10-02 2027-07-06 US US8377919 No 2013-02-19 2026-12-18 US US8372828 No 2013-02-12 2026-12-18 US US8372827 No 2013-02-12 2026-12-18 US US9789078 No 2017-10-17 2033-05-15 US US9820959 No 2017-11-21 2026-12-18 US US9833429 No 2017-12-05 2026-12-18 US US9833428 No 2017-12-05 2026-12-18 US US9861603 No 2018-01-09 2026-12-18 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.279 mg/mL ALOGPS logP 2.49 ALOGPS logP 2.51 Chemaxon logS -3.2 ALOGPS pKa (Strongest Acidic) 12.13 Chemaxon pKa (Strongest Basic) -2.8 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 104.06 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 117.86 m3·mol-1 Chemaxon Polarizability 47.14 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - 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 inhibitor Non-inhibitor 0.5257 CYP450 2D6 inhibitor Non-inhibitor 0.9137 CYP450 2C19 inhibitor Non-inhibitor 0.817 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-01q9-0005900000-cfe0403c6e1a4e8a38c8 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-ef55b0cd5e220e268bfb Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-01q9-0019100000-b309b9888fd9b49be136 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-9004200000-cfb7a8c918c2eb627e80 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0pb9-9011000000-45ad5d306b4725680784 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00ke-9102000000-5309597a6c25cab15e88 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
Drug created at October 21, 2007 22:23 / Updated at May 21, 2024 16:36