TRIFAROTENE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H33NO4
Molecular Weight	459.5766
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(C)C1=CC(=CC=C1N2CCCC2)C3=CC(=CC=C3OCCO)C4=CC=C(C=C4)C(O)=O

InChI

InChIKey=MFBCDACCJCDGBA-UHFFFAOYSA-N

InChI=1S/C29H33NO4/c1-29(2,3)25-19-23(10-12-26(25)30-14-4-5-15-30)24-18-22(11-13-27(24)34-17-16-31)20-6-8-21(9-7-20)28(32)33/h6-13,18-19,31H,4-5,14-17H2,1-3H3,(H,32,33)

HIDE SMILES / InChI

Molecular Formula	C29H33NO4
Molecular Weight	459.5766
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/29706423 | https://www.ncbi.nlm.nih.gov/pubmed/30141539 | https://www.ncbi.nlm.nih.gov/pubmed/31306527 | https://adisinsight.springer.com/drugs/800036364

Trifarotene is a novel first-in-class fourth-generation topical retinoid. It is a potent and selective RAR gamma-agonist. In multiple mouse models, trifarotene exhibited superior comedolytic, anti-inflammatory and depigmenting activity compared with other topical retinoids. In this 52-week study, trifarotene was safe, well-tolerated and effective in moderate facial and truncal acne. Trifarotene is in phase II clinical trial for the treatment of ichthyosis.

Originator

Approval Year

C_max

Value	Dose	Co-administered	Analyte	Population
12 pg/mL OTHER GOV https://www.fda.gov/media/132145/download	200 mg 1 times / day steady-state, topical dose: 200 mg route of administration: Topical experiment type: STEADY-STATE co-administered:		TRIFAROTENE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: UNKNOWN food status: UNKNOWN
10.8 pg/mL OTHER GOV https://www.fda.gov/media/132145/download	200 mg 1 times / day steady-state, topical dose: 200 mg route of administration: Topical experiment type: STEADY-STATE co-administered:		TRIFAROTENE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
137 pg × h/mL OTHER GOV https://www.fda.gov/media/132145/download	200 mg 1 times / day steady-state, topical dose: 200 mg route of administration: Topical experiment type: STEADY-STATE co-administered:		TRIFAROTENE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: UNKNOWN food status: UNKNOWN
118 pg × h/mL OTHER GOV https://www.fda.gov/media/132145/download	200 mg 1 times / day steady-state, topical dose: 200 mg route of administration: Topical experiment type: STEADY-STATE co-administered:		TRIFAROTENE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3 h OTHER GOV https://www.fda.gov/media/132145/download	200 mg 1 times / day steady-state, topical dose: 200 mg route of administration: Topical experiment type: STEADY-STATE co-administered:		TRIFAROTENE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
0.01 % 1 times / day multiple, topical Studied dose Dose: 0.01 %, 1 times / day Route: topical Route: multiple Dose: 0.01 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	unhealthy, 15 years (range: 12-17 years) Health Status: unhealthy Condition: acne vulgaris Age Group: 15 years (range: 12-17 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	DLT: Skin irritation... Other AEs: Skin exfoliation, Erythema... Dose limiting toxicities: Skin irritation (all grades, 8 patients) Other AEs: Skin exfoliation (all grades, 4 patients) Erythema (all grades, 4 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/32017149
0.01 % 1 times / day multiple, topical Studied dose Dose: 0.01 %, 1 times / day Route: topical Route: multiple Dose: 0.01 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	unhealthy, 20 years (range: 18-34 years) Health Status: unhealthy Condition: acne vulgaris Age Group: 20 years (range: 18-34 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	Other AEs: Skin irritation... Other AEs: Skin irritation (88.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/32017149
0.01 % 1 times / day multiple, topical Studied dose Dose: 0.01 %, 1 times / day Route: topical Route: multiple Dose: 0.01 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	unhealthy, 20 years (range: 18-34 years) n = 18 Health Status: unhealthy Condition: acne vulgaris Age Group: 20 years (range: 18-34 years) Sex: M+F Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/32017149	Other AEs: Erythema... Other AEs: Erythema (88.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/32017149
2 g 1 times / day multiple, topical Recommended Dose: 2 g, 1 times / day Route: topical Route: multiple Dose: 2 g, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211527s000lbl.pdf	unhealthy, >= 9 years n = 1220 Health Status: unhealthy Condition: acne vulgaris Age Group: >= 9 years Sex: M+F Population Size: 1220 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211527s000lbl.pdf	Other AEs: Application site irritation, Application site pruritus... Other AEs: Application site irritation (7.5%) Application site pruritus (2.4%) Sunburn (2.6%) Application site pain (< 1%) Application site dryness (< 1%) Application site discoloration (< 1%) Application site rash (< 1%) Application site swelling (< 1%) Application site erosion (< 1%) Erythema (< 1%) Dermatitis allergic (< 1%) Skin erythema (grade 1, 30.6%) Scale (grade 1, 37.5%) Dry skin face (grade 1, 39%) Stinging skin (grade 1, 35.6%) Skin erythema (grade 2, 28.4%) Scale (grade 2, 27.1%) Dry skin face (grade 2, 29.7%) Stinging skin (grade 2, 20.6%) Skin erythema (grade 3, 6.2%) Scale (grade 3, 4.9%) Dry skin face (grade 3, 4.8%) Stinging skin (grade 3, 5.9%) Skin erythema (grade 1, 26.5%) Skin scarring (grade 1, 29.7%) Dry skin (grade 1, 32.9%) Stinging skin (grade 1, 26.1%) Skin erythema (grade 2, 18.9%) Skin scarring (grade 2, 13.7%) Dry skin (grade 2, 16.1%) Stinging skin (grade 2, 10.9%) Skin erythema (grade 3, 5.2%) Skin scarring (grade 3, 1.7%) Dry skin (grade 3, 1.8%) Stinging skin (grade 3, 4.3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211527s000lbl.pdf
2 g 1 times / day multiple, topical Recommended Dose: 2 g, 1 times / day Route: topical Route: multiple Dose: 2 g, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf	unhealthy, >= 9 years n = 1220 Health Status: unhealthy Condition: acne vulgaris Age Group: >= 9 years Sex: M+F Population Size: 1220 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf	Disc. AE: Application site irritation, Application site erosion... AEs leading to discontinuation/dose reduction: Application site irritation (1.1%) Application site erosion (0.1%) Application site pain (0.1%) Acne (0.2%) Skin irritation (0.2%) Dermatitis allergic (0.1%) Bronchitis (0.1%) Muscle rupture (0.1%) Tibia fracture (0.1%) Major depression (0.1%) Suicide attempt (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf
0.02 % 2 times / week multiple, topical Highest studied dose Dose: 0.02 %, 2 times / week Route: topical Route: multiple Dose: 0.02 %, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/31713811/	unhealthy, adolescents; adults Health Status: unhealthy Condition: Lamellar Ichthyosis Age Group: adolescents; adults Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/31713811/	Sources: https://pubmed.ncbi.nlm.nih.gov/31713811/
12 g 2 times / week multiple, topical Highest studied dose Dose: 12 g, 2 times / week Route: topical Route: multiple Dose: 12 g, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf	healthy Health Status: healthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 CYP1A2 1524 CYP2B6 810 CYP2C19 1478 OAT 4 BCRP 699 P-gp 1461 BSEP 402 MRP 7	CYP2C8 693 CYP2B6 664 P-gp 1537 BCRP 561 OATP1B1/3 11 BSEP 52 MRP2 205 UGT 192	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	no
MRP 7	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	no
OAT 4	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	yes [IC50 2.78 uM]	unlikely Comment: approximately 140,000-fold higher than the Cmax of trifarotene (9.6 pg/mL equivalent to 0.00002µM) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	yes [IC50 3.9 uM]	unlikely Comment: approximately 140,000-fold higher than the Cmax of trifarotene (9.6 pg/mL equivalent to 0.00002µM) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0	yes [IC50 7.8 uM]	unlikely Comment: approximately 300,000-fold higher than the Cmax of trifarotene (9.6 pg/mL equivalent to 0.00002µM) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=171 Page: 171.0

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	major	unlikely Comment: The PBPK modeling predicted that Cmax and AUC of trifarotene could increase by 2.3- and 2.9-fold, respectively, if co-administered with strong CYP2C9 and CYP3A4 inhibitor. The simulated highest Cmax of trifarotene was markedly lower than the safety margin of trifarotene cream 50 µg/g. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=170 Page: 170.0	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	minor
UGT 192	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=43 Page: 43.0	minor
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0	minor	unlikely Comment: The PBPK modeling predicted that Cmax and AUC of trifarotene could increase by 2.3- and 2.9-fold, respectively, if co-administered with strong CYP2C9 and CYP3A4 inhibitor. The simulated highest Cmax of trifarotene was markedly lower than the safety margin of trifarotene cream 50 µg/g. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=59 Page: 59.0
BSEP 52	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=174 Page: 174.0	no
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=174 Page: 174.0	no
OATP1B1/3 11	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=174 Page: 174.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=174 Page: 174.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=174 Page: 174.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000MultidisclipineR.pdf#page=41 Page: 41.0

Sourcing

Vendor/Aggregator	ID	URL
Ambeed	A298564	https://www.ambeed.com/products/895542-09-3.html
BLD Pharm	BD00769386	http://www.bldpharm.com/products/895542-09-3.html
BOC Sciences	895542-09-3	https://www.bocsci.com/product/trifarotene-cas-895542-09-3-343568.html
BioChemPartner	BCP31392	http://www.biochempartner.com/895542-09-3-BCP31392
CSNpharm	CSN21330	https://www.csnpharm.com/products/trifarotene.html
Chem Scene	CS-0018407	http://www.chemscene.com/895542-09-3.html
Chemspace	CSSB00134614707	https://chem-space.com/CSSB00134614707
Excenen	EX-A2704	https://www.excenen.com/searchresultlist.php?id=895542-09-3
MedChem Express	HY-100256	https://www.medchemexpress.com/Trifarotene.html
Smolecule	S545843	http://www.smolecule.com/products/s545843
THE BioTek	bt-286834	https://www.thebiotek.com/product/inhibitors/bt-286834
eNovation Chemicals	D674183	https://www.enovationchem.com/ProductDetails.asp?ProductID=D674183

PubMed

Title	Date	PubMed
Topical trifarotene: a new retinoid.	2018 Aug	30141539
Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.	2018 Aug	29974453
Retinoids in Acne Management: Review of Current Understanding, Future Considerations, and Focus on Topical Treatments.	2018 Dec 1	30586483
Retinoids in Acne Management: Review of Current Understanding, Future Considerations, and Focus on Topical Treatments.	2018 Dec 1	30586482
Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne.	2018 Jun 1	29706423
Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne.	2019 Jun	30802558
Long-term safety and efficacy of trifarotene 50 μg/g cream, a first-in-class RAR-γ selective topical retinoid, in patients with moderate facial and truncal acne.	2020 Jan	31306527

Patents

Substance Class	Chemical Created by `admin` on `Sat Dec 16 01:45:45 GMT 2023` Edited by `admin` on `Sat Dec 16 01:45:45 GMT 2023`
Record UNII	0J8RN2W0HK
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

TRIFAROTENE

Official Name

English

TRIFAROTENE [ORANGE BOOK]

Common Name

English

CD-5789

Code

English

(1,1':3',1''-TERPHENYL)-4-CARBOXYLIC ACID, 3''-(1,1-DIMETHYLETHYL)-4'-(2-HYDROXYETHOXY)-4''-(1-PYRROLIDINYL)-

Systematic Name

English

Trifarotene [WHO-DD]

Common Name

English

CD5789

Code

English

TRIFAROTENE [MI]

Common Name

English

trifarotene [INN]

Common Name

English

TRIFAROTENE [USAN]

Common Name

English

3''-TERT-BUTYL-4'-(2-HYDROXYETHOXY)-4''-(PYRROLIDIN-1-YL)(1,1':3',1'')TERPHENYL-4-CARBOXYLIC ACID

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

431014