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HomeProduct name listIngenol mebutate

Ingenol mebutate

Ingenol mebutate Structural

What is Ingenol mebutate?

Absorption

Since ingenol mebutate is a topical treatment, the systemic absorption is less than 0.1 ng/mL.

Toxicity

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

Description

Ingenol mebutate (also known as PEP005) was approved in January 2012 by the US FDA for the topical treatment of actinic keratoses (AK). Ingenol mebutate also received approval in 2012 in the European Union, Australia, and Brazil for the same indication. Ingenol mebutate, a diterpene ester natural product, is the active agent in the sap of the plant Euphorbia peplus, which has long been used as a traditional remedy for skin lesions. Ingenol mebutate has a novel mechanism of action involving initial plasma membrane disruption, rapid loss of mitochondrial membrane potential, and cell death by primary necrosis within 1 h; a subsequent tumor-specific immune response results in antibodydependent cellular toxicity that eliminates residual cells. Ingenol mebutate is obtained by extraction from the dried, milled aerial parts of Euphorbia peplus followed by a series of purification steps.

Originator

Peplin (United States)

The Uses of Ingenol mebutate

Ingenol 3-Angelate is known to exhibit antitumor activities which induces plasma membrane and mitochondrial disruption and necrotic cell death.

The Uses of Ingenol mebutate

Ingenol 3-Angelate is used as a PKC activator, anticancer, and immunostimulant compound. It is also used to exhibits antileukemic activity, induces nuclear translocation of PKCδ, and induces apoptosis in acute myeloid leukemia (AML) cell lines and primary AML blast cells. Also displays antiproliferative effects and induces apoptosis in Colo205 cells.

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.

Indications

For the topical treatment of actinic keratosis.

What are the applications of Application

Ingenol 3-angelate is a PKC activator, anticancer, and immunostimulant compound

Definition

ChEBI: A tetracyclic diterpenoid ester obtained by formal condensation of the carboxy group of (2Z)-2-methylbut-2-enoic (angelic) acid with the 3-hydroxy group of ingenol. Used for the topical treatment of actinic keratosis.

brand name

Picato

Biochem/physiol Actions

Ingenol-3-angelate, is a phorbol ester-like compound or a diacylglycerol analog that is used in the treatment of several disorders like skin cancer. It is also known as PEP005. Ingenol-3-angelate stimulates the initiation of the enzyme by providing PKCs (protein kinase C) to cellular membranes.

Pharmacokinetics

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

Clinical Use

Ingenol mebutate is a diterpene ester which was approved in the US, EU, Austrailia, and Brazil for the treatment of actinic keratosis, a disease stage associated with sun exposure which can potentially develop into cancer. The drug, which is marketed by LEO Pharma A/S as Picato®, is administered as a topical gel (0.015%, 0.05%) which has been proven effective in treating face-, scalp-, and trunklocalized actinic keratosis in four randomized, double-blind, vehicle-controlled, multicenter studies. The drug exhibits mild side effects limited to application-site conditions (e. g. irritation, pain, pruritus), and no detectable concentrations of ingenol mebutate or two of its metabolites were found in blood samples.94 Traditionally used as a home remedy for various skin conditions, the ingenol mebutate, also referred to as ingenol 3-angelate, is the main active constituent of sap from the plant Euphorbia pelpus.95 From natural extractions, 17 kg of fresh E. pelpus afforded 7 g of ingenol 3-angelate as an oil, which upon further purification was deemed insufficient for process-scale production.

Synthesis

Although several synthetic approaches to the ingenol family of terpenes have been reported,97-113 Liang and coworkers at LEO Pharma have reported a semisynthesis of the API from naturally-occurring ingenol. This natural product?ˉs accessibility from the seeds of E. lathyris renders it widely commercial on scale. The conversion of ingenol to ingenol mebutate involves a protection, esterification, and deprotection strategy to procure scale quantities of the drug.114 Conversion of ingenol (87) to the corresponding 5,20-acetonide 88 proceeded in good yield using a protocol modified from the original conditions described by Hecker. A considerable amount of study was conducted by Liang to affect efficient angeloylation with minimal isomerization of the double-bond to the corresponding Z-isomer (tiglate). It was found that angelic anhydride 89 (which is a commercially available reagent, but for process scale was prepared immediately prior to usage from the self-condensation of 99.5% pure angelic acid with 0.5 equivalents of DCC) in the presence of LHMDS gave acetonide 90 in over 95% conversion and was practically free of the undesired tiglate bi-product after recrystallization (73% yield).96 Deprotection of the acetonide 90 was affected using phosphoric acid and after three recrystallizations, ingenol mebutate (XIV) was produced on multigram scale in a combined yield of 37% starting from ingenol 87.

Synthesis_75567-37-2

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.

storage

-20°C

References

References/Citations

Properties of Ingenol mebutate

Boiling point: 576.9±50.0 °C(Predicted)
Density  1.26±0.1 g/cm3(Predicted)
storage temp.  -20°C
solubility  DMSO: soluble15mg/mL, clear
pka 11.52±0.70(Predicted)
form  powder
color  white to beige
Water Solubility  Soluble in 100% ethanol, DMSO, dichloromethane, and methanol. Insoluble in water.
Stability: Stable for 1 year as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.

Safety information for Ingenol mebutate

Computed Descriptors for Ingenol mebutate

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