INGENOL DISOXATE

US Previously Marketed

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H37NO7
Molecular Weight	499.5959
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12C[C@@H](C)[C@]34C=C(C)[C@H](OC(=O)C5=C(CC)ON=C5CC)[C@@]3(O)[C@H](O)C(CO)=C[C@]([H])(C4=O)[C@]1([H])C2(C)C

InChI

InChIKey=GLIUZQUNUNICGS-XUBYYPQFSA-N

InChI=1S/C28H37NO7/c1-7-18-20(19(8-2)36-29-18)25(33)35-24-13(3)11-27-14(4)9-17-21(26(17,5)6)16(23(27)32)10-15(12-30)22(31)28(24,27)34/h10-11,14,16-17,21-22,24,30-31,34H,7-9,12H2,1-6H3/t14-,16+,17-,21+,22-,24+,27+,28+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C28H37NO7
Molecular Weight	499.5959
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	8 / 8
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202833s007lbl.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/25970561
Curator's Comment: http://www.dermnetnz.org/topics/ingenol-mebutate-gel/; http://www.ncbi.nlm.nih.gov/pubmed/25115145; https://www.ncbi.nlm.nih.gov/pubmed/?term=24672213; http://www.ncbi.nlm.nih.gov/pubmed/?term=26225771;

Ingenol is an extremely weak PKC (protein kinase C) activator, with potent anticancer activity. Ingenol derivatives have received constant and multidisciplinary attention on account of their pleiotropic pattern of biological activity. This includes activation of PKC (protein kinase C), tumor-promotion, anticancer, and anti-HIV properties, and the possibility of dissecting co-cancerogenic and clinically useful activities has been demonstrated. Certain ingenol esters show powerful anticancer activity, and a structure-activity relationship model to discriminate between their apoptotic and non-apoptotic properties has been developed.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Protein kinase C (PKC) 44 Target ID: CHEMBL2093867 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1727380	Activator 1430		30.0 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Unknown 2578
Actinic keratosis 11 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202833s007lbl.pdf	Curative		Approved 8429	PICATO Approved Use Indicated for the topical treatment of actinic keratosis. Launch Date 2012

C_max

Value	Dose	Co-administered	Analyte	Population
0.332 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28524709	0.127 mg 1 times / day multiple, topical dose: 0.127 mg route of administration: Topical experiment type: MULTIPLE co-administered:		INGENOL MEBUTATE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1.43 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28524709	0.127 mg 1 times / day multiple, topical dose: 0.127 mg route of administration: Topical experiment type: MULTIPLE co-administered:		INGENOL MEBUTATE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
0.015 % 1 times / day multiple, topical Recommended Dose: 0.015 %, 1 times / day Route: topical Route: multiple Dose: 0.015 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52	unhealthy, 61 years n = 1 Health Status: unhealthy Age Group: 61 years Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52	Disc. AE: Eye pain, Application site pain... AEs leading to discontinuation/dose reduction: Eye pain (severe, 1 patient) Application site pain (severe, 1 patient) Periorbital edema (severe, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52
0.25 % 1 times / day multiple, topical Highest studied dose Dose: 0.25 %, 1 times / day Route: topical Route: multiple Dose: 0.25 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	unhealthy n = 1 Health Status: unhealthy Condition: superficial basal cell carcinoma Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	Disc. AE: Lymphangitis... AEs leading to discontinuation/dose reduction: Lymphangitis (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53
0.05 % 1 times / day multiple, topical Recommended Dose: 0.05 %, 1 times / day Route: topical Route: multiple Dose: 0.05 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	unhealthy n = 1 Health Status: unhealthy Condition: nodular basal cell carcinoma Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	Disc. AE: Erythema, Skin exfoliation... AEs leading to discontinuation/dose reduction: Erythema (1 patient) Skin exfoliation (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53

AEs

AE	Significance	Dose	Population
Application site pain	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended Dose: 0.015 %, 1 times / day Route: topical Route: multiple Dose: 0.015 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52	unhealthy, 61 years n = 1 Health Status: unhealthy Age Group: 61 years Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52
Eye pain	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended Dose: 0.015 %, 1 times / day Route: topical Route: multiple Dose: 0.015 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52	unhealthy, 61 years n = 1 Health Status: unhealthy Age Group: 61 years Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52
Periorbital edema	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended Dose: 0.015 %, 1 times / day Route: topical Route: multiple Dose: 0.015 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52	unhealthy, 61 years n = 1 Health Status: unhealthy Age Group: 61 years Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 52
Lymphangitis	1 patient Disc. AE	0.25 % 1 times / day multiple, topical Highest studied dose Dose: 0.25 %, 1 times / day Route: topical Route: multiple Dose: 0.25 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	unhealthy n = 1 Health Status: unhealthy Condition: superficial basal cell carcinoma Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53
Erythema	1 patient Disc. AE	0.05 % 1 times / day multiple, topical Recommended Dose: 0.05 %, 1 times / day Route: topical Route: multiple Dose: 0.05 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	unhealthy n = 1 Health Status: unhealthy Condition: nodular basal cell carcinoma Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53
Skin exfoliation	1 patient Disc. AE	0.05 % 1 times / day multiple, topical Recommended Dose: 0.05 %, 1 times / day Route: topical Route: multiple Dose: 0.05 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53	unhealthy n = 1 Health Status: unhealthy Condition: nodular basal cell carcinoma Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000MedR.pdf Page: p. 53

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	inhibitor 1767 inducer 389	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882	P-gp 1537	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174892/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202833Orig1s000PharmR.pdf#page=24 Page: 24.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:66913	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:66913
ZINC	ZINC000056898854	http://zinc15.docking.org/substances/ZINC000056898854

PubMed

Title	Date	PubMed
Characterization of the interaction of ingenol 3-angelate with protein kinase C.	2004 May 1	15126366
Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate.	2006 Dec 1	17114487
HIV type 1 inhibition by protein kinase C modulatory compounds.	2006 Sep	16989610
PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study.	2009 Feb	19178487
Ingenol mebutate gel for actinic keratosis.	2012 Mar 15	22417254
Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui.	2017 Aug 25	28842560

Patents

Sample Use Guides

In Vivo Use Guide

For application of up to one contiguous skin area of approximately 25 cm^2 (5 cm x 5 cm) using one unit dose tube. For actinic keratosis on the face or scalp apply Picato gel, 0.015% to the affected area once daily for 3 consecutive days. For actinic keratosis on the trunk or extremities apply Picato gel 0.05% to the affected area once daily for 2 consecutive days

Route of Administration: Topical

In Vitro Use Guide

Unknown

Substance Class	Chemical Created by `admin` on `Sat Dec 16 10:50:58 GMT 2023` Edited by `admin` on `Sat Dec 16 10:50:58 GMT 2023`
Record UNII	3B100VJ4ZW
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

INGENOL DISOXATE

Official Name

English

(1aR,2S,3Z,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 3,5-diethylisoxazole-4-carboxylate

Systematic Name

English

Ingenol disoxate [WHO-DD]

Common Name

English

LEO43204

Code

English

ingenol disoxate [INN]

Common Name

English

LEO-43204

Code

English

INGENOL DISOXATE [USAN]

Common Name

English

INGENOL 3-(3,5-DIETHYLISOXAZOLE-4-CARBOXYLATE)

Common Name

English

4-ISOXAZOLECARBOXYLIC ACID, 3,5-DIETHYL-, (1AR,2S,5R,5AS,6S,8AS,9R,10AR)-1A,2,5,5A,6,9,10,10A-OCTAHYDRO-5,5A-DIHYDROXY-4-(HYDROXYMETHYL)-1,1,7,9-TETRAMETHYL-11-OXO-1H-2,8A-METHANOCYCLOPENTA(A)CYCLOPROPA(E)CYCLODECEN-6-YL ESTER

Systematic Name

English

Code System Code Type Description

NCI_THESAURUS

C123379