ATRASENTAN HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H38N2O6.ClH
Molecular Weight	547.083
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CCCCN(CCCC)C(=O)CN1C[C@@H]([C@H]([C@@H]1C2=CC=C(OC)C=C2)C(O)=O)C3=CC4=C(OCO4)C=C3

InChI

InChIKey=IJFUJIFSUKPWCZ-SQMFDTLJSA-N

InChI=1S/C29H38N2O6.ClH/c1-4-6-14-30(15-7-5-2)26(32)18-31-17-23(21-10-13-24-25(16-21)37-19-36-24)27(29(33)34)28(31)20-8-11-22(35-3)12-9-20;/h8-13,16,23,27-28H,4-7,14-15,17-19H2,1-3H3,(H,33,34);1H/t23-,27-,28+;/m1./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

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

Molecular Formula	C29H38N2O6
Molecular Weight	510.6218
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://adisinsight.springer.com/drugs/800008541
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/8632312

Atrasentan (ABT-627, A-127722) is a selective endothelin A receptor antagonist. Atrasentan is being developed by AbbVie as an oral treatment for diabetic nephropathies.Abbott Laboratories was conducting clinical development of atrasentan for the treatment of certain cancers, including phase II trials for prostate cancer. However, no recent development has been reported for cancer indications and development is presumed to be discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Endothelin receptor ET-A 19 Target ID: CHEMBL252 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8632312	Antagonist 2778		69.0 pM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Diabetic nephropathy 35 Sources: http://adisinsight.springer.com/drugs/800008541	Primary		Phase III 656	Unknown Approved Use Unknown
Prostate cancer 178 Sources: http://adisinsight.springer.com/drugs/800008541	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
89 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	5 mg 1 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.28 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.12 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	1.75 mg single, oral dose: 1.75 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.72 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	0.75 mg single, oral dose: 0.75 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
242 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	30 mg 1 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
358 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	20 mg 1 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
489 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	75 mg 1 times / day multiple, oral dose: 75 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
819 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
544 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	45 mg 1 times / day multiple, oral dose: 45 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
62 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
580 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	5 mg 1 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.71 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
13.07 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	1.75 mg single, oral dose: 1.75 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.31 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21372210	0.75 mg single, oral dose: 0.75 mg route of administration: Oral experiment type: SINGLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1492 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	30 mg 1 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1591 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	20 mg 1 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2338 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	75 mg 1 times / day multiple, oral dose: 75 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3162 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5354 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	45 mg 1 times / day multiple, oral dose: 45 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
536 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
34.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	5 mg 1 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
32 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	30 mg 1 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
40.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	20 mg 1 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
36.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	75 mg 1 times / day multiple, oral dose: 75 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
32.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
30 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	45 mg 1 times / day multiple, oral dose: 45 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
23.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1.2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15240529	75 mg 1 times / day multiple, oral dose: 75 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ATRASENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
75 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15240529	unhealthy n = 9 Health Status: unhealthy Condition: Refractory Malignancies Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/15240529	DLT: hyponatremia, hypotension... Dose limiting toxicities: hyponatremia (severe, 2 patients) hypotension (serious, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/15240529
70 mg 1 times / day multiple, oral (unknown) MTD Dose: 70 mg, 1 times / day Route: oral Route: multiple Dose: 70 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18477765	unhealthy n = 11 Health Status: unhealthy Condition: malignant glioma Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/18477765	Other AEs: low white blood count, Constipation... Other AEs: low white blood count (2 patients) Constipation (1 pt) Platelets decreased (1 pt) Nausea (1 pt) Arthralgia (1 pt) glutamic pyruvic transaminase increase (1 pt) Vomiting (1 pt) absolute neutrophil count (1 pt) Hypocalcemia (2 patients) Weight gain (1 pt) Dry mouth (1 pt) Headache (2 patients) Dyspnea (2 patients) Allergic rhinitis (4 patients) Edema (5 patients) Fatigue (3 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/18477765
0.75 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 0.75 mg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24722445	unhealthy n = 78 Health Status: unhealthy Condition: diabetic neuropathy Sex: M+F Food Status: UNKNOWN Population Size: 78 Sources: https://pubmed.ncbi.nlm.nih.gov/24722445	Disc. AE: acute appendicitis, lung hemorrhage... AEs leading to discontinuation/dose reduction: acute appendicitis (1 pt) lung hemorrhage (1 pt) fatigue (1 pt) Peripheral edema (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/24722445
1.25 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 1.25 mg, 1 times / day Route: oral Route: multiple Dose: 1.25 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24722445	unhealthy n = 83 Health Status: unhealthy Condition: diabetic neuropathy Sex: M+F Food Status: UNKNOWN Population Size: 83 Sources: https://pubmed.ncbi.nlm.nih.gov/24722445	Disc. AE: Hypoglycemia, hyperkalemia... Other AEs: Atheroma coronary artery... AEs leading to discontinuation/dose reduction: Hypoglycemia (1 pt) hyperkalemia (1 pt) hyperkalemia (2 patients) Other AEs: Atheroma coronary artery (1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/24722445
90 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 90 mg, 1 times / day Route: oral Route: multiple Dose: 90 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18477765	unhealthy n = 3 Health Status: unhealthy Condition: malignant glioma Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/18477765	DLT: peripheral edema, peripheral edema... Dose limiting toxicities: peripheral edema (grade 3, 1 pt) peripheral edema (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/18477765

AEs

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P0038NU	https://www.1pchem.com/search?query=1P0038NU
AChemBlock	O32832	http://www.achemblock.com/catalogsearch/result/?q=O32832
Angene	AGN-PC-0WH6AV	http://www.angenechemical.com/productshow/AGN-PC-0WH6AV.html
BLD Pharm	BD630447	http://www.bldpharm.com/search/Search.html?keyword=BD630447
BOC Sciences	173937-91-2	http://www.bocsci.com/description.asp?cas=173937-91-2
BOC Sciences	195733-43-8	http://www.bocsci.com/description.asp?cas=195733-43-8
Chem Scene	CS-1373	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-1373
ChemShuttle	178789	https://www.chemshuttle.com/catalogsearch/result/?q=178789
Hairui	ATXF025	http://www.hairuichem.com/en/product/search.do?q=ATXF025
MedChem Express	HY-15403A	https://www.medchemexpress.com/search.html?q=HY-15403A&ft=&fa=&fp=
MolPort	MolPort-044-724-665	https://www.molport.com/shop/molecule-link/MolPort-044-724-665
MuseChem	I002268	https://www.musechem.com/product/I002268.html
MuseChem	I003252	https://www.musechem.com/product/I003252.html
MuseChem	I014016	https://www.musechem.com/product/I014016.html
PI Chemicals	PI-41907	http://www.pipharm.com/catalog_products/PI-41907.html
Sigma Aldrich	SML2020	http://www.sigmaaldrich.com/catalog/search?term=SML2020&interface=All&N=0&mode=match%20partialmax&lang=en®ion=US&focus=product
Toronto Research Chemicals	A793925	https://www.trc-canada.com/product-detail/?CatNum=A793925
Toronto Research Chemicals	A793930	https://www.trc-canada.com/product-detail/?CatNum=A793930
eMolecules	271447644	https://orderbb.emolecules.com/search/#?query=271447644
eMolecules	29917658	https://orderbb.emolecules.com/search/#?query=29917658
eMolecules	50282664	https://orderbb.emolecules.com/search/#?query=50282664
mcule	MCULE-1574445963	https://mcule.com/MCULE-1574445963/
mcule	MCULE-4362237304	https://mcule.com/MCULE-4362237304/
mcule	MCULE-5848986494	https://mcule.com/MCULE-5848986494/
mcule	MCULE-6900549695	https://mcule.com/MCULE-6900549695/

PubMed

Title	Date	PubMed
Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist.	1996 Feb	8632312
Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer.	1996 Feb 15	8630991
2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722.	1996 Mar 1	8676339
Endothelin and blood pressure regulation in the female rat: studies in normal pregnancy and with nitric oxide synthase inhibition-induced hypertension.	2000	10877991
Effect of castration on endothelin receptors.	2002 Aug	12193141
ABT-627, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma growth in vitro.	2002 Aug	12193113
Endothelins regulate mediator production of rat tissue-cultured mucosal mast cells. Up-regulation of Th1 and inhibition of Th2 cytokines.	2002 May	11994508
Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension.	2003 Feb 25	12600921
Endothelin receptors as novel targets in tumor therapy.	2004 May 27	15165288
Differential roles of peripheral and spinal endothelin receptors in the micturition reflex in rats.	2004 Oct	15371886
Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma.	2006 Dec	17032313
Endothelin receptor antagonists.	2006 Jun	16219361
Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism.	2007 Jan	17167119
Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.	2008 Dec	18823320
DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum.	2008 Jun	18516094
Phase I/II study of atrasentan, an endothelin A receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer.	2008 Mar 1	18316570
Protective effects of angiotensin AT1 receptor blockade in malignant hypertension in the rat.	2009 Apr 1	19326569
Development and evaluation of endothelin-A receptor (radio)ligands for positron emission tomography.	2011 Feb 24	21275367
Endothelin 1 activation of endothelin A receptor/NADPH oxidase pathway and diminished antioxidants critically contribute to endothelial progenitor cell reduction and dysfunction in salt-sensitive hypertension.	2012 May	22431579
Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: role of endothelin signaling.	2015 Apr 1	25656942

Patents

Sample Use Guides

In Vivo Use Guide

0.75, or 1.75 mg daily for 8 weeks atrasentan is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.

Route of Administration: Oral

In Vitro Use Guide

Atrasentan (ABT-627, A-127722) exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:26:45 GMT 2023` Edited by `admin` on `Fri Dec 15 15:26:45 GMT 2023`
Record UNII	E4G31X93ZA
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ATRASENTAN HYDROCHLORIDE

Official Name

English

(2R,3R,4S)-1-((DIBUTYLCARBAMOYL)METHYL)-2-(P-METHOXYPHENYL)-4-(3,4-(METHYLENEDIOXY)PHENYL)-3-PYRROLIDINECARBOXYLIC ACID, MONOHYDROCHLORIDE

Common Name

English

ATRASENTAN HCL

Common Name

English

A-147627.1

Code

English

ATRASENTAN HYDROCHLORIDE [USAN]

Common Name

English

ABBOT-147627

Code

English

ABT-627

Code

English

ATRASENTAN HYDROCHLORIDE [MART.]

Common Name

English

ATRASENTAN HYDROCHLORIDE [MI]

Common Name

English

3-PYRROLIDINECARBOXYLIC ACID, 4-(1,3-BENZODIOXOL-5-YL)-1-(2-(DIBUTYLAMINO)-2-OXOETHYL)-2-(4-METHOXYPHENYL)-, MONOHYDROCHLORIDE, (2R-(2.ALPHA.,3.BETA.,4.ALPHA.))

Common Name

English

Atrasentan hydrochloride [WHO-DD]

Common Name

English

Code System Code Type Description

NCI_THESAURUS

C1779