Ingenol

Ingenol mebutate

Clinical data
Trade names	Picato
Synonyms	PEP005, ingenol-3-angelate
AHFS/Drugs.com	picato
License data	EU EMA: by INN
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Topical (gel)
ATC code	D06BX02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	Below detection level
Identifiers
IUPAC name (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-Dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen-6-yl (2Z)-2-methylbut-2-enoate
CAS Number	75567-37-2
PubChem CID	6918670
ChemSpider	26325194
ChEBI	CHEBI:66913 Y
ECHA InfoCard	100.214.695
Chemical and physical data
Formula	C25H34O6
Molar mass	430.534 g/mol
3D model (JSmol)	Interactive image
SMILES C/C=C(/C)\C(=O)O[C@H]1C(C)=C[C@]23[C@]1(O)[C@H](O)C(CO)=C[C@H](C3=O)[C@H]4[C@H](C4(C)C)C[C@H]2C
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 Key:VDJHFHXMUKFKET-WDUFCVPESA-N

Ingenol mebutate (ingenol-3-angelate, PEP005, LEO Pharma trade name Picato) is a substance found in the sap of the plant Euphorbia peplus and an inducer of cell death. A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the topical treatment of actinic keratosis. Two different strengths of the gel are approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively.

Results from four multicenter, randomized, double-blind studies have shown that ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses.

Irritations of the application site are very common. This includes redness, scaling, crusting, pain, pruritus, and sometimes infection. Other side effects include eye irritation such as periorbital edema (3% of patients in studies), headache (2%) and nasopharyngitis (running nose, 2%).

Allergic reactions or shingles may also occur.

As ingenol mebutate is practically not absorbed through the skin, interactions with oral drugs are unlikely.

The substance is an ester of the diterpene ingenol and angelic acid. A 3-step semisynthesis of ingenol mebutate starting from ingenol was described. A 14-step synthesis of (+)-ingenol from (+)-3-carene, which is a relatively inexpensive constituent of turpentine, was published in July 2013.

Ingenol mebutate has also been found to be useful for reactivating latent HIV virus in cells taken from individuals who have tested negative for signs of the disease following extended courses of anti-retroviral drugs, raising the possibility that this drug may be used to expose the last traces of virus, and thus potentially provide a permanent cure for HIV infection. Research is ongoing to determine whether the effects observed in vitro are also seen in animal models, with a view to eventual human trials for this application.