ATOPAXAR

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H38FN3O5
Molecular Weight	527.6275
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOC1=CC2=C(C(=N)N(CC(=O)C3=CC(N4CCOCC4)=C(OC)C(=C3)C(C)(C)C)C2)C(F)=C1OCC

InChI

InChIKey=QWKAUGRRIXBIPO-UHFFFAOYSA-N

InChI=1S/C29H38FN3O5/c1-7-37-23-15-19-16-33(28(31)24(19)25(30)27(23)38-8-2)17-22(34)18-13-20(29(3,4)5)26(35-6)21(14-18)32-9-11-36-12-10-32/h13-15,31H,7-12,16-17H2,1-6H3

HIDE SMILES / InChI

Molecular Formula	C29H38FN3O5
Molecular Weight	527.6275
Charge	0
Count

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

Description
Sources: http://adisinsight.springer.com/drugs/800019681
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/22871190 | https://www.ncbi.nlm.nih.gov/pubmed/25135289 |https://www.ncbi.nlm.nih.gov/pubmed/21300059

Atopaxar, also known as E 5555 is a novel reversible protease-activated receptor-1 (PAR-1) thrombin receptor antagonist. The inhibition of thrombin-mediated platelet activation by means of protease-activated receptor-1 inhibitors represents an attractive therapeutic option for patients with atherothrombotic disease processes. In preclinical studies, atopaxar demonstrated inhibition of thrombin receptor-activating peptides (TRAP)- and thrombin-induced platelet aggregation. Atopaxar was being developed by Eisai for acute coronary syndromes (ACS) and coronary disorders, including atherothrombosis, unstable angina pectoris and myocardial infarction. Atopaxar was in phase II clinical development in the US, EU and Japan. However, development was discontinued in May 2012.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Proteinase-activated receptor 1 5 Target ID: CHEMBL3974 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21300059/	Antagonist 2778		19.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute coronary syndrome 33 Sources: http://adisinsight.springer.com/drugs/800019681	Primary		Phase II 1132	Unknown Approved Use Unknown
Coronary artery disease 48 Sources: http://adisinsight.springer.com/drugs/800019681	Primary		Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
200 mg 1 times / day multiple, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21502571 Page: p.1858	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: coronary artery disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/21502571 Page: p.1858	Disc. AE: Bleeding... AEs leading to discontinuation/dose reduction: Bleeding (1.61%) Sources: https://pubmed.ncbi.nlm.nih.gov/21502571 Page: p.1858
200 mg 1 times / day multiple, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21502577 Page: p.1848	unhealthy, ADULT n = 148 Health Status: unhealthy Condition: coronary artery disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 148 Sources: https://pubmed.ncbi.nlm.nih.gov/21502577 Page: p.1848	Sources: https://pubmed.ncbi.nlm.nih.gov/21502577 Page: p.1848

AEs

AE	Significance	Dose	Population
Bleeding	1.61% Disc. AE	200 mg 1 times / day multiple, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21502571 Page: p.1858	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: coronary artery disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/21502571 Page: p.1858

Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677557	inconclusive [IC50 18.3564 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363677557	yes [IC50 5.3547 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363677557	yes [IC50 6.0081 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363677557	yes [IC50 7.5637 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/32241309/	major

PubMed

Title	Date	PubMed
The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease.	2009 Jul	19572075
Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease.	2010 Nov	20805115
The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs.	2011 Apr 25	21300059
Atopaxar: a review of its mechanism of action and role in patients with coronary artery disease.	2012 Jul	22871190

Patents

Sample Use Guides

In Vivo Use Guide

In phase 2 study : Patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD) received Atopaxar (E5555) (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition.

Route of Administration: Oral

In Vitro Use Guide

Platelet inhibition was usually moderate, present already at 20 ng/ml of Atopaxar (E5555), and was not seemingly dose-dependent without TRAP stimulation. E5555 caused 10-15% inhibition of ADP- and collagen-induced platelet aggregation in plasma, but not in whole blood. TRAP-induced aggregation was inhibited almost completely. PECAM-I, GP IIb/IIIa antigen, and activity with PAC-1, GPIb, thrombospondin, vitronectin receptor expression, and formation of platelet-monocyte aggregates were also significantly reduced by E5555. TRAP stimulation caused dose-dependent effects between 20 and 50 ng/ml E5555 doses.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 18:45:09 UTC 2023` Edited by `admin` on `Fri Dec 15 18:45:09 UTC 2023`
Record UNII	HTI275SD2D
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ATOPAXAR

Official Name

English

E-5555

Code

English

ATOPAXAR [USAN]

Common Name

English

2-(5,6-DIETHOXY-7-FLUORO-1-IMINO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)-1-(3-(1,1-DIMETHYLETHYL)- 4-METHOXY-5-(MORPHOLIN-4-YL)PHENYL)ETHANONE

Systematic Name

English

atopaxar [INN]

Common Name

English

Atopaxar [WHO-DD]

Common Name

English

ER-172594-00

Code

English

ETHANONE, 2-(5,6-DIETHOXY-7-FLUORO-1,3-DIHYDRO-1-IMINO-2H-ISOINDOL-2-YL)-1-(3-(1,1- DIMETHYLETHYL)-4-METHOXY-5-(4-MORPHOLINYL)PHENYL)-

Systematic Name

English

2-(5,6-DIETHOXY-7-FLUORO-1-IMINO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)-1-(3-TERT-BUTYL-4-METHOXY-5-(MORPHOLIN-4-YL)PHENYL)ETHAN-1-ONE

Systematic Name

English

E5555

Code

English

Code System Code Type Description

SMS_ID

100000175108