BENOXAPROFEN

US Previously Marketed

First approved in 1982

Details

Stereochemistry	RACEMIC
Molecular Formula	C16H12ClNO3
Molecular Weight	301.724
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C(O)=O)C1=CC2=C(OC(=N2)C3=CC=C(Cl)C=C3)C=C1

InChI

InChIKey=MITFXPHMIHQXPI-UHFFFAOYSA-N

InChI=1S/C16H12ClNO3/c1-9(16(19)20)11-4-7-14-13(8-11)18-15(21-14)10-2-5-12(17)6-3-10/h2-9H,1H3,(H,19,20)

HIDE SMILES / InChI

Description
Sources: https://www.federalregister.gov/documents/2013/06/04/2013-13053/eli-lilly-and-co-withdrawal-of-approval-of-a-new-drug-application-for-oraflex | https://www.bmj.com/content/bmj/285/6340/459.full.pdf

BENOXAPROFEN is an anti-inflammatory drug indicated for the treatment of arthritis. It was marketed under the brand name ORAFLEX® in the US and as OPREN® in Europe by Eli Lilly and Company. In 1982 Eli Lilly voluntarily withdrew BENOXAPROFEN from the market due to postmarketing reports of severe liver toxicity in patients who took it.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Arachidonate 5-lipoxygenase 49 Target ID: CHEMBL215 Sources: http://drugcentral.org/drugcard/311\|https://www.ncbi.nlm.nih.gov/pubmed/2988019\|https://www.ncbi.nlm.nih.gov/pubmed/2572437\|https://www.ncbi.nlm.nih.gov/pubmed/6131964\|https://www.genome.jp/dbget-bin/www_bget?dr:D03080	Inhibitor 8297		149.0 µM [IC50]
Bile salt export pump 15 Target ID: CHEMBL2073674 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21965623	Inhibitor 8297		99.1 µM [IC50]

C_max

Value	Dose	Co-administered	Analyte	Population
43 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/303114	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BENOXAPROFEN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
94 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/6930484	300 mg 2 times / day steady-state, rectal dose: 300 mg route of administration: Rectal experiment type: STEADY-STATE co-administered:		BENOXAPROFEN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
503 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/303114	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		BENOXAPROFEN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.84 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/303114	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		BENOXAPROFEN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
38 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/6930484	300 mg 2 times / day steady-state, rectal dose: 300 mg route of administration: Rectal experiment type: STEADY-STATE co-administered:		BENOXAPROFEN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
600 mg 1 times / day steady, oral Recommended Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6407402/	unhealthy, 35 years (rage: 26-43 years) n = 20 Health Status: unhealthy Condition: arthritis Age Group: 35 years (rage: 26-43 years) Sex: M+F Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/6407402/	Disc. AE: Photosensitivity... AEs leading to discontinuation/dose reduction: Photosensitivity (11 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6407402/
900 mg 1 times / day steady, oral Highest studied dose Dose: 900 mg, 1 times / day Route: oral Route: steady Dose: 900 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6803978	unhealthy, 54,9 years (range: 18-86 years) n = 5 Health Status: unhealthy Age Group: 54,9 years (range: 18-86 years) Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/6803978	Sources: https://pubmed.ncbi.nlm.nih.gov/6803978

AEs

AE	Significance	Dose	Population
Photosensitivity	11 patient Disc. AE	600 mg 1 times / day steady, oral Recommended Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6407402/	unhealthy, 35 years (rage: 26-43 years) n = 20 Health Status: unhealthy Condition: arthritis Age Group: 35 years (rage: 26-43 years) Sex: M+F Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/6407402/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
		CYP1A1 108 CYP1A2 701 CYP4A1 17

Drug as perpetrator

Target	Modality	Activity
CYP1A1 218	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/2069584/	yes
CYP1A2 1692	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/2069584/	yes
CYP4A1 25	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/2069584/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:76114	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:76114
eMolecules	35875742	https://www.emolecules.com/cgi-bin/more?vid=35875742

PubMed

Title	Date	PubMed
Nonsteroid anti-inflammatory agents: regulators of the phagocytic secretion of lysosomal enzymes from guinea-pig neutrophils.	1978 Nov	712644
An update on long-term efficacy and safety with benoxaprofen.	1982	7084281
The preferential inhibition of 5-lipoxygenase product formation by benoxaprofen.	1983 Jan	6131964
The aetiology of psoriasis: clues provided by benoxaprofen.	1983 Jul	6305387
Interaction of benoxaprofen with rat erythrocytes: effects on oxidative metabolism and membrane ATPase activities.	1986 Nov	2947294
In vitro inhibition of leukotriene B4 formation by exogeneous 5-lipoxygenase inhibitors is associated with enhanced generation of 15-hydroxy-eicosatetraenoic acid (15-HETE) by human neutrophils.	1988	2849922
Species difference of 5-lipoxygenase derived from polymorphonuclear leukocytes on sensitivity to drugs.	1989 May	2724698
Induction of the cytochrome P450 I and IV families and peroxisomal proliferation in the liver of rats treated with benoxaprofen. Possible implications in its hepatotoxicity.	1991 Jun 21	2069584
Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs.	1993 Jan	8423545
A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.	2006 Apr	16456879
Glucuronidation and covalent protein binding of benoxaprofen and flunoxaprofen in sandwich-cultured rat and human hepatocytes.	2009 Dec	19773537
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192

Patents

Name

Type

Language

BENOXAPROFEN

Official Name

English

COMPD 90459

Code

English

benoxaprofen [INN]

Common Name

English

BENOXAPROFEN [MART.]

Common Name

English

OPREN

Brand Name

English

COMPOUND-90459

Code

English

BENOXAPROFEN [JAN]

Common Name

English

5-BENZOXAZOLEACETIC ACID, 2-(4-CHLOROPHENYL)-.ALPHA.-METHYL, (±)-

Common Name

English

Benoxaprofen [WHO-DD]

Common Name

English

BENOXAPROFEN [USAN]

Common Name

English

COMPOUND 90459

Code

English

BENOXAPROFEN [MI]

Common Name

English

NSC-299582

Code

English

(±)-2-(P-CHLOROPHENYL)-.ALPHA.-METHYL-5-BENZOXAZOLEACETIC ACID

Common Name

English

COXIGON

Brand Name

English

ORAFLEX

Brand Name

English

Classification Tree Code System Code

WHO-VATC

QM01AE06