EFINACONAZOLE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H22F2N4O
Molecular Weight	348.3903
Optical Activity	( - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](N1CCC(=C)CC1)[C@](O)(CN2C=NC=N2)C3=CC=C(F)C=C3F

InChI

InChIKey=NFEZZTICAUWDHU-RDTXWAMCSA-N

InChI=1S/C18H22F2N4O/c1-13-5-7-23(8-6-13)14(2)18(25,10-24-12-21-11-22-24)16-4-3-15(19)9-17(16)20/h3-4,9,11-12,14,25H,1,5-8,10H2,2H3/t14-,18-/m1/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf
Curator's Comment: description was created based on several sources, including

Efinaconazole is triazole used as a 10% topical solution for the treatment of onychomycosis, a fungal infection of the nails. It was approved for use in Canada and the USA in 2014 and is marketed by Valeant Pharmaceuticals North America LLC under the name Jublia. Like other antifungal triazoles, efinaconazole inhibits the fungal cytochrome P450 enzyme lanosterol 14α demethylase (CYP51), thereby disrupting ergosterol synthesis and, consequently, membrane integrity and growth in fungi. CYP51 is evolutionarily conserved and, in mammals, mediates conversion of lanosterol to meiosis-activating sterols (MAS); MAS are intermediates in the biosynthesis of cholesterol and may have a signaling role in initiating meiosis and oocyte maturation. Azoles have higher affinity for fungal CYP51 compared to the mammalian enzyme and such selectivity contributes to the safety of this therapeutic class. Azoles have been reported to produce reproductive and developmental toxicity in both humans and laboratory animals. The mechanism is unknown but inhibition of mammalian CYP51 as well as other CYPs, e.g. CYP17, CYP19 and CYP26, have been postulated to play a role.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Lanosterol 14-alpha demethylase 13 Target ID: CHEMBL3307221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23459486	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Onychomycosis 18 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf	Curative		Approved 8429	JUBLIA Approved Use Indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes. Launch Date 2014

C_max

Value	Dose	Co-administered	Analyte	Population
0.55 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203567s009lbl.pdf	42 mg 1 times / day multiple, topical dose: 42 mg route of administration: Topical experiment type: MULTIPLE co-administered:		EFINACONAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: UNKNOWN food status: UNKNOWN
0.67 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203567s009lbl.pdf	42 mg 1 times / day multiple, topical dose: 42 mg route of administration: Topical experiment type: MULTIPLE co-administered:		EFINACONAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
11.4 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203567s009lbl.pdf	42 mg 1 times / day multiple, topical dose: 42 mg route of administration: Topical experiment type: MULTIPLE co-administered:		EFINACONAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: UNKNOWN food status: UNKNOWN
12.15 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203567s009lbl.pdf	42 mg 1 times / day multiple, topical dose: 42 mg route of administration: Topical experiment type: MULTIPLE co-administered:		EFINACONAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
29.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203567s009lbl.pdf	42 mg 1 times / day multiple, topical dose: 42 mg route of administration: Topical experiment type: MULTIPLE co-administered:		EFINACONAZOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
3.85% OTHER GOV https://pdf.hres.ca/dpd_pm/00054721.PDF			EFINACONAZOLE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
10 % 1 times / day multiple, topical Recommended Dose: 10 %, 1 times / day Route: topical Route: multiple Dose: 10 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.108	healthy, adult n = 239 Health Status: healthy Age Group: adult Population Size: 239 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.108	Other AEs: Coronary artery disease, Seizure... Other AEs: Coronary artery disease (0.4%) Seizure (0.4%) Large intestine infection (0.4%) Pneumonia (0.4%) Numbness in leg (0.4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.108
10 % 1 times / day multiple, topical Recommended Dose: 10 %, 1 times / day Route: topical Route: multiple Dose: 10 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103	unhealthy, mean age 51 years n = 1227 Health Status: unhealthy Condition: onychomycosis Age Group: mean age 51 years Sex: M+F Population Size: 1227 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103	Disc. AE: Acute psychosis, Application site eczema... AEs leading to discontinuation/dose reduction: Acute psychosis (0.1%) Application site eczema (0.2%) Application site erythema (0.3%) Application site exfoliation (0.1%) Application site irritation (0.2%) Application site pain (0.1%) Application site pruritus (0.2%) Application site reaction (0.1%) Application site swelling (0.2%) Application site vesicles (0.5%) Blood glucose abnormal (0.1%) Dermatitis (0.1%) Dermatitis contact (0.2%) Headache (0.1%) Intracranial aneurysm (0.1%) Lung squamous cell carcinoma stage unspecified (0.1%) Lymphadenopathy (0.1%) Prostate cancer (0.1%) Extrasystoles ventricular (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103
10 % 1 times / day multiple, topical Recommended Dose: 10 %, 1 times / day Route: topical Route: multiple Dose: 10 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103	unhealthy, mean age 51 years n = 1227 Health Status: unhealthy Condition: onychomycosiss Age Group: mean age 51 years Sex: M+F Population Size: 1227 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103	Disc. AE: Application site dermatitis... AEs leading to discontinuation/dose reduction: Application site dermatitis (1.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.103
10 % 1 times / day multiple, topical Recommended Dose: 10 %, 1 times / day Route: topical Route: multiple Dose: 10 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.104	unhealthy, mean age 51 years n = 1227 Health Status: unhealthy Condition: onychomycosis Age Group: mean age 51 years Sex: M+F Population Size: 1227 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.104	Other AEs: Application site dermatitis, Application site vesicles... Other AEs: Application site dermatitis (2.2%) Application site vesicles (1.6%) Application site pain (1.1%) Ingrowing nail (2.3%) Contact dermatitis (2.2%) Eczema (2%) Rash (1.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000MedR.pdf Page: /nda/2014/203567Orig1s000MedR.pdf - p.104

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 CYP2C19 1478 CYP1A2 1524 CYP2A6 707 CYP2E1 882 CYP2B6 810	CYP2C19 991	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no [IC50 46.1 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no [IC50 >100 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	yes [IC50 0.194 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	yes [IC50 0.731 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	yes [IC50 1.36 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	yes
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=17 Page: 17.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=7 Page: 7.0	major
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000ClinPharmR.pdf#page=7 Page: 7.0	major

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203567Orig1s000PharmR.pdf#page=28 Page: 28.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:82718	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82718
ChemicalBook	CB21313343	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB21313343
MolPort	MolPort-039-139-376	https://www.molport.com/shop/molecule-link/MolPort-039-139-376
ZINC	ZINC000000006251	http://zinc15.docking.org/substances/ZINC000000006251

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

10% solution for topical application once daily for 48 weeks

Route of Administration: Topical

In Vitro Use Guide

Efinaconazole exhibits in vitro minimum inhibitory concentrations (MICs) of 0.06 μg/mL or less against most (≥90%) isolates of the following microorganisms: Trichophyton rubrum and Trichophyton mentagrophytes.

Name

Type

Language

EFINACONAZOLE

Official Name

English

Efinaconazole [WHO-DD]

Common Name

English

IDP-108

Code

English

EFINACONAZOLE [ORANGE BOOK]

Common Name

English

CLENAFIN

Brand Name

English

EFINACONAZOLE [JAN]

Common Name

English

1-PIPERIDINEETHANOL, .ALPHA.-(2,4-DIFLUOROPHENYL)-.BETA.-METHYL-4-METHYLENE-.ALPHA.-(1H-1,2,4-TRIAZOL-1-YLMETHYL)-,(.ALPHA.R,.BETA.R)-

Common Name

English

JUBLIA

Brand Name

English

(2R,3R)-2-(2,4-DIFLUOROFENIL)-3-(4-METILENOPIPERIDIN-1-IL)-1-(1H-1,2,4-TRIAZIN-1-IL)BUTAN-2-OL

Common Name

English

EFINACONAZOLE [MI]

Common Name

English

KP-103

Code

English

1-PIPERIDINEETHANOL, .ALPHA.-(2,4-DIFLUOROPHENYL)-.BETA.-METHYL-4-METHYLENE-.ALPHA.-(1H-1,2,4-TRIAZOL-1-YLMETHYL)-, (R-(R*,R*))-

Common Name

English

efinaconazole [INN]

Common Name

English

EFINACONAZOLE [USAN]

Common Name

English

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Systematic Name

English

EFINACONAZOLE [VANDF]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175487