INGENOL DISOXATE

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

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	MOL RATIO 1 MOL RATIO (average)

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

Description

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	Activator 1,430		30.0 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Unknown 2,578
Actinic keratosis 11	Curative		Approved 8,429	PICATO

C_max

Value	Dose	Co-administered	Analyte	Population
0.332 nM	0.127 mg 1 times / day multiple, topical		INGENOL MEBUTATE blood	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1.43 ng × h/mL	0.127 mg 1 times / day multiple, topical		INGENOL MEBUTATE blood	Homo sapiens

Doses

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Dose	Population	Adverse events
0.015 % 1 times / day multiple, topical Recommended	unhealthy, 61 years n = 1	Disc. AE: Eye pain, Application site pain...
0.25 % 1 times / day multiple, topical Highest studied dose	unhealthy n = 1	Disc. AE: Lymphangitis...
0.05 % 1 times / day multiple, topical Recommended	unhealthy n = 1	Disc. AE: Erythema, Skin exfoliation...

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AEs

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AE	Significance	Dose	Population
Application site pain	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended	unhealthy, 61 years n = 1
Eye pain	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended	unhealthy, 61 years n = 1
Periorbital edema	severe, 1 patient Disc. AE	0.015 % 1 times / day multiple, topical Recommended	unhealthy, 61 years n = 1
Lymphangitis	1 patient Disc. AE	0.25 % 1 times / day multiple, topical Highest studied dose	unhealthy n = 1
Erythema	1 patient Disc. AE	0.05 % 1 times / day multiple, topical Recommended	unhealthy n = 1

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882	P-gp 1,537	CYP1A2 701

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inhibitor 3,277	no
CYP2B6 1,001	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1,537	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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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

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PubMed

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Title	Date	PubMed
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

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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
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

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Code System

Code

Type

Description

NCI_THESAURUS

C123379

PRIMARY

FDA UNII

3B100VJ4ZW

PRIMARY

SMS_ID

100000174968

PRIMARY

DRUG BANK

DB15109

PRIMARY

PUBCHEM

57410862

PRIMARY

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Related Record

Type

Details


					IC77UZI9G8

INGENOL

ACTIVE MOIETY

Amount:

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

Drug as perpetrator