ETODOLAC, (R)-

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H21NO3
Molecular Weight	287.3535
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC1=CC=CC2=C1NC3=C2CCO[C@]3(CC)CC(O)=O

InChI

InChIKey=NNYBQONXHNTVIJ-QGZVFWFLSA-N

InChI=1S/C17H21NO3/c1-3-11-6-5-7-12-13-8-9-21-17(4-2,10-14(19)20)16(13)18-15(11)12/h5-7,18H,3-4,8-10H2,1-2H3,(H,19,20)/t17-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C17H21NO3
Molecular Weight	287.3535
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2939246 | https://www.ncbi.nlm.nih.gov/pubmed/6227748 | https://www.ncbi.nlm.nih.gov/pubmed/15699354 | http://cancerres.aacrjournals.org/content/64/7_Supplement/847.2 | https://www.ncbi.nlm.nih.gov/pubmed/17275129 | http://adisinsight.springer.com/drugs/800016689 | http://en.pharmacodia.com/web/drug/1_5430.html

R-etodolac (SDX-101) is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid). The absolute configuration of the enantiomer is R-(-)-etodolac. R-etodolac specifically bound retinoid X receptor (RXRalpha), inhibited RXRalpha transcriptional activity, and induced its degradation by a ubiquitin and proteasome-dependent pathway. In addition R-etodolac can disrupt the beta-catenin signaling pathway. R-etodolac exerts antineoplastic properties. R-etodolac was in phase 2 studies for the treatment of hematologic malignancies however development was discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Retinoid X receptor alpha 11 Target ID: CHEMBL2061 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15699354	Inhibitor 8297		200.0 µM [IC50]
Catenin beta-1 3 Target ID: CHEMBL5866 Sources: http://cancerres.aacrjournals.org/content/64/7_Supplement/847.2 \| https://www.ncbi.nlm.nih.gov/pubmed/17275129	Inhibitor 8297		200.0 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple myeloma 159 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15802527 https://www.ncbi.nlm.nih.gov/pubmed/17849446	Primary		Phase II 1132	Unknown Approved Use Unknown
Chronic lymphocytic leukemia 59 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17169808 https://www.ncbi.nlm.nih.gov/pubmed/17186240	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
85.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
106.4 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	2400 mg 2 times / day multiple, oral dose: 2400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
543.3 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
768.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	2400 mg 2 times / day multiple, oral dose: 2400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
5.76 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.94 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18094935	2400 mg 2 times / day multiple, oral dose: 2400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ETODOLAC, (R)- plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478	UGT1A4 347 CYP2B6 664 UGT1A10 291 UGT2B7 389 CYP1A2 1054 CYP2C8 693 UGT2B15 203 UGT1A3 422 UGT1A8 283 CYP2A6 543 UGT1A7 236 UGT1A6 307 CYP2C19 991 UGT1A1 418 CYP2E1 667 UGT1A9 380 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/410#sid=11112763	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/899#sid=11112763	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/883#sid=11112763	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/891#sid=11112763	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/885#sid=11112763	no

Drug as victim

Target	Modality	Activity
UGT1A3 422	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	likely
UGT1A6 307	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	likely
UGT1A9 380	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	likely
UGT2B7 389	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	likely
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	major
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	minor
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680117	no
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no
UGT1A10 291	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no
UGT1A4 347	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no
UGT1A7 236	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no
UGT1A8 283	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no
UGT2B15 203	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15370961/	no

PubMed

Title	Date	PubMed
Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers.	1983 Dec	6227748
Pharmacokinetic difference between S-(+)- and R-(-)-etodolac in rats.	2004 Aug	15301730
SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma.	2005 Jul 15	15802527
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942

Patents

Sample Use Guides

In Vivo Use Guide

Phase 2, multi-center, open label, randomized clinical study for the treatment chronic lymphocytic leukaemia: R-etodolac 600mg tablets + chlorambucil 2mg tablets for 24-26 weeks

Route of Administration: Oral

In Vitro Use Guide

R-etodolac induced significant cytotoxicity in MM.1S, U266, RPMI8226, INA-6, and OPM1 MM cell lines with IC50 of 0.49, 1.06, 0.54, 0.22, and 0.47 mM, respectively. R-etodolac also triggers cytotoxicity, with IC50 of 0.62, 0.76 and 0.62 mM, respectively, in Dex-resistant MM.1R, Dox-resistant RPMI-Dox40, and bortezomib-resistant DHL4 cells32. Importantly, R-etodolac does not induce cytotoxicity in PBMCs from 3 healthy volunteers with concentrations as high as 2.5 mM

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:42:40 GMT 2023` Edited by `admin` on `Fri Dec 15 15:42:40 GMT 2023`
Record UNII	Y1RAH31T6K
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ETODOLAC, (R)-

Common Name

English

(-)-ETODOLAC

Common Name

English

R-ETODOLAC

Common Name

English

(1R)-1,8-DIETHYL-1,3,4,9-TETRAHYDROPYRANO(3,4-B)INDOLE-1-ACETIC ACID

Systematic Name

English

PYRANO(3,4-B)INDOLE-1-ACETIC ACID, 1,8-DIETHYL-1,3,4,9-TETRAHYDRO-, (1R)-

Common Name

English

KS-1056

Code

English

RAK-593

Code

English

ETODOLAC, (-)-

Common Name

English

SDX-101

Code

English

(-)-(R)-ETODOLAC

Common Name

English

PYRANO(3,4-B)INDOLE-1-ACETIC ACID, 1,8-DIETHYL-1,3,4,9-TETRAHYDRO-, (R)-

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

162702