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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H22N2O6
Molecular Weight 410.4199
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DARUSENTAN

SMILES

COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C2=CC=CC=C2)C3=CC=CC=C3)=N1

InChI

InChIKey=FEJVSJIALLTFRP-LJQANCHMSA-N
InChI=1S/C22H22N2O6/c1-27-17-14-18(28-2)24-21(23-17)30-19(20(25)26)22(29-3,15-10-6-4-7-11-15)16-12-8-5-9-13-16/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1

HIDE SMILES / InChI

Molecular Formula C22H22N2O6
Molecular Weight 410.4199
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: the description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19748665 | https://www.ncbi.nlm.nih.gov/pubmed/17917503 | https://www.ncbi.nlm.nih.gov/pubmed/15276394 | https://www.ncbi.nlm.nih.gov/pubmed/14734123 | https://www.drugbank.ca/drugs/DB04883

Darusentan is an orally active, propanoic acid-based endothelin receptor antagonist (ERA) that selectively blocks endothelin-1 (ET-1) binding to the endothelin type-A (ETA) receptor. Darusentan exhibited subnanomolar binding affinity and approximately 1000-fold selectivity for the ETA receptor in binding experiments conducted in vitro under steady-state conditions. Darusentan is orally bioavailable and, when administered to humans, maximum plasma concentrations are observed within 1–2 h post dosing. The mean elimination half-life is relatively long (>15 h), which is consistent with once-daily dosing. Darusentan is primarily glucuronidated by Phase II enzymes in the liver, and the major route of elimination of Darusentan and its metabolites is via the bile. Some glucuronidated metabolites of Darusentan are also excreted in the urine. Darusentan doses up to 300 mg/day were well tolerated and associated with a manageable safety profile in patients with resistant hypertension (RHTN). The most frequently reported adverse events in Ddarusentan-treated subjects were peripheral edema (17%) and headache (11%), which were mostly mild or moderate in severity. Other commonly reported adverse events in the Darusentan treatment group were sinusitis (8%), dizziness (7%), upper respiratory tract infection (5%) and gastroenteritis (5%). In phase III clinical trial the mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg with placebo, 17/10 mm Hg with Darusentan 50 mg, 18/10 mm Hg with Darusentan 100 mg, and 18/11 mm Hg with Darusentan 300 mg. Unfortunately, phase III clinical trial evaluating Darusentan did not achieve its co-primary efficacy endpoints of achieving a change in systolic and diastolic blood pressure after 14 weeks compared to a placebo. Perhaps for this reason, shortly after the top-line results of this study became known, the sponsor announced that Darusentan would not be developed further for resistant hypertension.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.8 nM [IC50]
16.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
300 mg 1 times / day multiple, oral
Highest studied dose
Dose: 300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 300 mg, 1 times / day
Sources: Page: p.766, 767
unhealthy, ADULT
n = 76
Health Status: unhealthy
Condition: hypertension
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 76
Sources: Page: p.766, 767
Disc. AE: Peripheral edema...
AEs leading to
discontinuation/dose reduction:
Peripheral edema (grade 1-2)
Sources: Page: p.766, 767
AEs

AEs

AESignificanceDosePopulation
Peripheral edema grade 1-2
Disc. AE
300 mg 1 times / day multiple, oral
Highest studied dose
Dose: 300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 300 mg, 1 times / day
Sources: Page: p.766, 767
unhealthy, ADULT
n = 76
Health Status: unhealthy
Condition: hypertension
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 76
Sources: Page: p.766, 767
PubMed

PubMed

TitleDatePubMed
Effects of endothelin a receptor blockade on endothelial function in patients with chronic heart failure.
2001 Feb 20
Darusentan (Abbott Laboratories).
2001 Nov
Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.
2001 Nov
Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent.
2001 Nov
Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure.
2002 Aug
Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin.
2002 Aug
Pharmacological prevention and regression of arterial remodeling in a rat model of isolated systolic hypertension.
2002 Aug
Chronic ET(A) receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice.
2002 Feb 1
Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.
2002 Jan 1
Gateways to clinical trials.
2002 Jan-Feb
Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension.
2002 Jul
Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs.
2002 Jul
Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).
2002 Nov 19
Endothelin-A receptor blockade prevents left ventricular hypertrophy and dysfunction in salt-sensitive experimental hypertension.
2002 Oct 29
Renal damage is not improved by blockade of endothelin receptors in primary renin-dependent hypertension.
2003 Dec
Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice.
2003 Feb
Effects of the endothelin a receptor antagonist darusentan on blood pressure and vascular contractility in type 2 diabetic Goto-Kakizaki rats.
2003 Jun
Gateways to clinical trials. March 2003.
2003 Mar
Nephroprotective effects of the endothelin ET(A) receptor antagonist darusentan in salt-sensitive genetic hypertension.
2003 May 16
Gateways to clinical trials.
2003 Sep
Endothelin-A receptor antagonist reduces microcirculatory disturbances and transplant dysfunction after partial liver transplantation.
2003 Sep
Endothelin receptor antagonists in heart failure: current status and future directions.
2004
Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition.
2004 Dec
Neurohumoral and hemodynamic effects of the selective endothelin antagonist darusentan in advanced chronic heart failure.
2004 Jan
Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.
2004 Jul 24-30
Phenotypic modulation of vascular smooth muscle cells during medial arterial calcification: a role for endothelin?
2004 Nov
Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism.
2004 Nov
Effects of chronic endothelin ET(A) receptor blockade on blood pressure and vascular formation of cyclic guanosine-3',5'-monophosphate in spontaneously hypertensive rats.
2005
Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats.
2005 Aug 1
Gateways to clinical trials.
2005 Dec
Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase.
2005 Sep 13
Endothelin-1 receptor antagonist (LU-135252) improves the microcirculation and course of TNBS colitis in rats.
2006 Aug
Gateways to clinical trials.
2006 Dec
Gateways to clinical trials.
2006 Jun
Downregulation of renal endothelin-converting enzyme 2 expression in early autoimmune diabetes.
2006 Jun
Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug.
2006 Jun
Endothelin receptor antagonists.
2006 Jun
Endothelin ETA receptor blockade with darusentan increases sodium and potassium excretion in aging rats.
2006 Mar
Spironolactone preserves cardiac norepinephrine reuptake in salt-sensitive Dahl rats.
2006 May
New drugs for hypertension: what do they offer?
2006 Oct
Up-regulated inflammatory factors endothelin, NFkappaB, TNFalpha and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats.
2006 Oct 4
Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin receptors.
2007 Nov
Darusentan: a new perspective for treatment of resistant hypertension?
2008 Aug
Dietary alkalinization and darusentan for prevention of decline in glomerular filtration rate in rats fed a casein diet.
2008 Dec
Efficacy and safety of darusentan: a novel endothelin receptor antagonist.
2008 Jul
Clinical approach in treatment of resistant hypertension.
2009
Vasodilators in the treatment of acute heart failure: what we know, what we don't.
2009 Dec
Darusentan, a selective endothelin A receptor antagonist, for the oral treatment of resistant hypertension.
2010 Aug
Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes.
2010 Jun
Gene expression of endothelin-1 and endothelin receptor a on monocrotaline-induced pulmonary hypertension in rats after bosentan treatment.
2010 Sep
Patents

Patents

Sample Use Guides

10, 50, 100, 150, and 300 mg once daily for 10 weeks
Route of Administration: Oral
The binding studies were performed using CHO cells stably expressing human ETA or ETB receptors. Membrane protein (10-50 µg) was incubated for 30 min at 25 °C in 50 mM Tris-HCl, pH 7.4, containing 5 mM MnCl2, 40 µg/mL bacitracin, and 0.2% BSA, with 25 pM [125I]ET-1 (ETA assay) or 25 pM [125I]ET-3 (ETB assay) in the presence or absence of the Darusentan. Nonspecific binding was measured with 0.1 µM ET-1.
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:51:54 GMT 2023
Edited
by admin
on Fri Dec 15 15:51:54 GMT 2023
Record UNII
33JD57L6RW
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
DARUSENTAN
INN   MI   WHO-DD  
INN  
Official Name English
BENZENEPROPANOIC ACID, .ALPHA.-((4,6-DIMETHOXY-2-PYRIMIDINYL)OXY)-.BETA.-METHOXY-.BETA.-PHENYL-, (S)-
Common Name English
(+)-(S)-2-((4,6-DIMETHOXY-2-PYRIMIDINYL)OXY)-3-METHOXY-3,3-DIPHENYLPROPIONIC ACID
Systematic Name English
darusentan [INN]
Common Name English
HMR-4005
Code English
Darusentan [WHO-DD]
Common Name English
DARUSENTAN [MI]
Common Name English
LU-135252
Code English
Classification Tree Code System Code
NCI_THESAURUS C270
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
Code System Code Type Description
FDA UNII
33JD57L6RW
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
WIKIPEDIA
DARUSENTAN
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
SMS_ID
100000126181
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
DRUG BANK
DB04883
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
CAS
171714-84-4
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
NCI_THESAURUS
C75991
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
EVMPD
SUB32910
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
PUBCHEM
177236
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
MERCK INDEX
m4100
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY Merck Index
EPA CompTox
DTXSID1057664
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
INN
7838
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
ChEMBL
CHEMBL23261
Created by admin on Fri Dec 15 15:51:54 GMT 2023 , Edited by admin on Fri Dec 15 15:51:54 GMT 2023
PRIMARY
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