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
Structure for Darusentan (DB04883)
- 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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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.
Target Actions Organism UEndothelin-1 receptor Not Available Humans - 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- 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
- 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]
- 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]
- Gradman AH, Vivas Y: New drugs for hypertension: what do they offer? Curr Hypertens Rep. 2006 Oct;8(5):425-32. [Article]
- External Links
- PubChem Compound
- 177236
- PubChem Substance
- 175426886
- ChemSpider
- 154336
- BindingDB
- 50108202
- ChEMBL
- CHEMBL23261
- ZINC
- ZINC000003826221
- Wikipedia
- Darusentan
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Hypertension 2 3 Terminated Treatment Hypertension 2 2 Completed Treatment Coronary Artery Disease (CAD) / Endothelial Dysfunction 1 2 Completed Treatment 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
Property Value Source Water Solubility 0.0994 mg/mL ALOGPS logP 3.61 ALOGPS logP 4.38 Chemaxon logS -3.6 ALOGPS pKa (Strongest Acidic) 3.2 Chemaxon pKa (Strongest Basic) 0.83 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 100 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 108.54 m3·mol-1 Chemaxon Polarizability 41.18 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8864 Blood Brain Barrier + 0.9233 Caco-2 permeable - 0.531 P-glycoprotein substrate Non-substrate 0.6679 P-glycoprotein inhibitor I Non-inhibitor 0.8558 P-glycoprotein inhibitor II Non-inhibitor 0.9571 Renal organic cation transporter Non-inhibitor 0.9123 CYP450 2C9 substrate Non-substrate 0.7224 CYP450 2D6 substrate Non-substrate 0.8142 CYP450 3A4 substrate Substrate 0.5167 CYP450 1A2 substrate Inhibitor 0.5574 CYP450 2C9 inhibitor Non-inhibitor 0.6086 CYP450 2D6 inhibitor Non-inhibitor 0.9465 CYP450 2C19 inhibitor Non-inhibitor 0.5545 CYP450 3A4 inhibitor Non-inhibitor 0.9317 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6908 Ames test Non AMES toxic 0.678 Carcinogenicity Non-carcinogens 0.8934 Biodegradation Not ready biodegradable 0.8825 Rat acute toxicity 2.5008 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9964 hERG inhibition (predictor II) Non-inhibitor 0.9608
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-005i-0029100000-24d77d61584cdf8a25e4 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0119000000-00d15d093dab1451dca1 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-057r-5916000000-038d8a57c68f0760d39a Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a6r-1893100000-e089183f0f2972588d10 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-7941000000-07f390bf0c51628b76e7 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-0900000000-28a022dad82beae3d470 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 212.3277579 predictedDarkChem Lite v0.1.0 [M-H]- 186.47276 predictedDeepCCS 1.0 (2019) [M+H]+ 213.1426579 predictedDarkChem Lite v0.1.0 [M+H]+ 188.86833 predictedDeepCCS 1.0 (2019) [M+Na]+ 212.6583579 predictedDarkChem Lite v0.1.0 [M+Na]+ 194.78085 predictedDeepCCS 1.0 (2019)
Targets
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- 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
- 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]
- 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