Identification

Generic Name
Darusentan
DrugBank Accession Number
DB04883
Background

Darusentan is a selective endothelin ETA receptor antagonist. It is being evaluated as a treatment for congestive heart failure and hypertension.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 410.4199
Monoisotopic: 410.147786446
Chemical Formula
C22H22N2O6
Synonyms
  • Darusentan
External IDs
  • LU 135252
  • LU-135252

Pharmacology

Indication

For the treatment of congestive heart failure and hypertension.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Darusentan is a selective endothelin ETA receptor antagonist.

Mechanism of action

The mode of action by which the endothelin receptor antagonists cause a decrease of the BP is not yet totally elucidated; however, peripheral vasodilatation due to blockade of the vasoconstrictor effects of endothelin is the most likely explanation. A reduction of cardiac contractility is considered unlikely. Several studies have been published that investigated the effects of either selective or nonselective endothelin receptor blockade in patients with heart failure. In these studies, application of endothelin antagonists, while decreasing both systemic and pulmonary BP increased cardiac index and did not alter cardiac contractility or heart rate.

TargetActionsOrganism
UEndothelin-1 receptorNot AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Phenylpropanoic acids / Benzylethers / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Monosaccharides / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Dialkyl ethers / Carboxylic acids / Azacyclic compounds
show 5 more
Substituents
3-phenylpropanoic-acid / Alkyl aryl ether / Aromatic heteromonocyclic compound / Azacycle / Benzylether / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Dialkyl ether / Diphenylmethane
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
33JD57L6RW
CAS number
171714-84-4
InChI Key
FEJVSJIALLTFRP-LJQANCHMSA-N
InChI
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
IUPAC Name
(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
SMILES
COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C2=CC=CC=C2)C2=CC=CC=C2)=N1

References

General References
  1. Black HR, Bakris GL, Weber MA, Weiss R, Shahawy ME, Marple R, Tannoury G, Linas S, Wiens BL, Linseman JV, Roden R, Gerber MJ: Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J Clin Hypertens (Greenwich). 2007 Oct;9(10):760-9. [Article]
  2. Kruschewski M, Anderson T, Loddenkemper C, Buhr HJ: Endothelin-1 receptor antagonist (LU-135252) improves the microcirculation and course of TNBS colitis in rats. Dig Dis Sci. 2006 Aug;51(8):1461-70. Epub 2006 Jul 26. [Article]
  3. Gradman AH, Vivas Y: New drugs for hypertension: what do they offer? Curr Hypertens Rep. 2006 Oct;8(5):425-32. [Article]
PubChem Compound
177236
PubChem Substance
175426886
ChemSpider
154336
BindingDB
50108202
ChEMBL
CHEMBL23261
ZINC
ZINC000003826221
Wikipedia
Darusentan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHigh Blood Pressure (Hypertension)2
3TerminatedTreatmentHigh Blood Pressure (Hypertension)2
2CompletedTreatmentCoronary Artery Disease (CAD) / Endothelial Dysfunction1
2CompletedTreatmentHigh Blood Pressure (Hypertension)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0994 mg/mLALOGPS
logP3.61ALOGPS
logP4.38Chemaxon
logS-3.6ALOGPS
pKa (Strongest Acidic)3.2Chemaxon
pKa (Strongest Basic)0.83Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area100 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity108.54 m3·mol-1Chemaxon
Polarizability41.18 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8864
Blood Brain Barrier+0.9233
Caco-2 permeable-0.531
P-glycoprotein substrateNon-substrate0.6679
P-glycoprotein inhibitor INon-inhibitor0.8558
P-glycoprotein inhibitor IINon-inhibitor0.9571
Renal organic cation transporterNon-inhibitor0.9123
CYP450 2C9 substrateNon-substrate0.7224
CYP450 2D6 substrateNon-substrate0.8142
CYP450 3A4 substrateSubstrate0.5167
CYP450 1A2 substrateInhibitor0.5574
CYP450 2C9 inhibitorNon-inhibitor0.6086
CYP450 2D6 inhibitorNon-inhibitor0.9465
CYP450 2C19 inhibitorNon-inhibitor0.5545
CYP450 3A4 inhibitorNon-inhibitor0.9317
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6908
Ames testNon AMES toxic0.678
CarcinogenicityNon-carcinogens0.8934
BiodegradationNot ready biodegradable0.8825
Rat acute toxicity2.5008 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9964
hERG inhibition (predictor II)Non-inhibitor0.9608
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Details
1. Endothelin-1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is:...
Gene Name
EDNRA
Uniprot ID
P25101
Uniprot Name
Endothelin-1 receptor
Molecular Weight
48721.76 Da
References
  1. Orth SR, Schiele G, Banas B, Ritz E, Amann K: Effect of a selective endothelin receptor A blocker on cardiovascular remodeling in uninephrectomized spontaneously hypertensive rats of the stroke-prone strain. Kidney Blood Press Res. 2007;30(6):400-7. Epub 2007 Sep 20. [Article]
  2. Xia QG, Reinecke A, Dorenkamp M, Daemen MJ, Simon R, Unger T: Effects of endothelin ETA receptor blocker LU 135252 on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure. Acta Pharmacol Sin. 2006 Nov;27(11):1417-22. [Article]

Drug created at October 21, 2007 11:37 / Updated at February 21, 2021 18:51