Therapeutic Targets Database
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TTD Target ID: TTDS00198

Target Information
NameEndothelin-1 receptor    
Type of targetSuccessful target    
SynonymsET-A    
ETA receptor    
ETA-R    
Endothelin A receptor    
Endothelin receptor A    
HET-AR    
DiseaseAtopic asthma
[ICD9: 493   ICD10: J45]
[1]
Cardiovascular disease, unspecified
[ICD9: 390-459   ICD10: I00-I99]
[2]
Chronic renal failure
[ICD9: 585.9585.1-585.5403   ICD10: N18]
[3]
Hypertension
[ICD9: 401   ICD10: I10, I11, I12, I13, I15]
[2]
Ovarian cancer
[ICD9: 183   ICD10: C56]
[4]
Drug(s)AmbrisentanApprovedPulmonary arterial hypertension[5]
BosentanApprovedPulmonary arterial hypertension[6]
SitaxsentanMarketedPulmonary arterial hypertension[7]
AvosentanPhase IIIDiabetic nephropathy[8][9]
PF-1228305Phase IIIPulmonary Hypertension[10]
ZibotentanPhase IIIHormone resistant prostate cancer[11]
AtrasentanWithdrawn in NDAHormone-refractory prostate cancer[12]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayCalcium signaling pathway
Neuroactive ligand-receptor interaction
Vascular smooth muscle contraction
UniProt IDP25101
FunctionReceptor 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: ET1 > ET2 >> ET3.    
SequenceMETLCLRASFWLALVGCVISDNPERYSTNLSNHVDDFTTFRGTELSFLVTTHQPTNLVLP SNGSMHNYCPQQTKITSAFKYINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIA SLALGDLIYVVIDLPINVFKLLAGRWPFDHNDFGVFLCKLFPFLQKSSVGITVLNLCALS VDRYRAVASWSRVQGIGIPLVTAIEIVSIWILSFILAIPEAIGFVMVPFEYRGEQHKTCM LNATSKFMEFYQDVKDWWLFGFYFCMPLVCTAIFYTLMTCEMLNRRNGSLRIALSEHLKQ RREVAKTVFCLVVIFALCWFPLHLSRILKKTVYNEMDKNRCELLSFLLLMDYIGINLATM NSCINPIALYFVSKKFKNCFQSCLCCCCYQSKSLMTSVPMNGTSIQWKNHDQNNHNTDRS SHKDSMN
Related US Patent6,358,983
6,387,915
6,509,341
6,670,362
Target ValidationClick to Find Target Validation Information.    
Inhibitor2-HYDROXY-3,5-DIIODOBENZOIC ACID[13]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[14]
Ac-W-F-F-N-Y-Y-W[15]
Ac-bhg-F-N-Y-Y-W[15]
Ac-w-F-F-N-Y-Y-W[15]
BMS-182874[16]
BMS-187308[16]
BMS-193884[16]
BMS-248360[17]
BOSENTAN SODIUM[18]
PD-155080[19]
PD-156707[20]
PD-163140[19]
Trp-Ile-Ile-Asp-Leu-Hisc (Cys-Ser-Val-Tyr-Phe-Cys)[21]
Trp-Ile-Ile-Asp-Leu-Hisc (Cys-Val-Tyr-Phe-Cys)[21]
W-F-F-N--Y-Y-W[15]
asterric acid[22]
bhg-F-N-Y-Y-W[15]
endothelin-1[23]
endothelin-2[23]
AntagonistABT-627[4]
Ambrisentan[5]
Atrasentan[12]
Avosentan[8][9]
BQ-123[24][25]
BQ610[26]
Bosentan[6]
FR139317[27]
LU302146[2]
LU302872[2]
PD142893[26]
PD156707[28]
PF-1228305[10]
Sitaxsentan[7]
TBC 11251 (TBC)[29]
Zibotentan[11]
MultitargetBosentan[6]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Variants of endothelin-1 and its receptors in atopic asthma. Biochem Biophys Res Commun. 1999 Aug 19;262(1):259-62. To Reference
Ref 2Influence of endothelin receptor antagonists on myocardial protein kinase C isoforms in uraemic cardiomyopathy. Clin Sci (Lond). 2002 Aug;103 Suppl 48:276S-279S. To Reference
Ref 3Endothelin-1 in chronic renal failure and hypertension. Can J Physiol Pharmacol. 2003 Jun;81(6):607-21. To Reference
Ref 4Therapeutic targeting of the endothelin a receptor in human ovarian carcinoma. Cancer Res. 2003 May 15;63(10):2447-53. To Reference
Ref 5GSK. Product Development Pipeline. February 2009. To Reference
Ref 6Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii25-31. To Reference
Ref 7Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19. To Reference
Ref 8Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63. To Reference
Ref 9Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers. Int J Clin Pharmacol Ther. 2006 Dec;44(12):668-74. To Reference
Ref 10Pfizer. Product Development Pipeline. March 31 2009. To Reference
Ref 11AstraZeneca. Product Development Pipeline. January 29 2009. To Reference
Ref 12Effects of a selective ET(A)-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity. Clin Sci (Lond). 2002 Aug;103 Suppl 48:367S-370S. To Reference
Ref 13Blandin V, Vigne P, Breittmayer JP, Frelin C: Allosteric inhibition of endothelin ETA receptors by 3, 5-dibromosalicylic acid. Mol Pharmacol. 2000 Dec;58(6):1461-9. To Reference
Ref 14J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential. To Reference
Ref 15Bioorg. Med. Chem. Lett. 5(6):621-626 (1995) To Reference
Ref 16J Med Chem. 2000 Aug 10;43(16):3111-7.Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists. To Reference
Ref 17J Med Chem. 2005 Oct 20;48(21):6523-43.Designed multiple ligands. An emerging drug discovery paradigm. To Reference
Ref 18J Med Chem. 2001 Oct 11;44(21):3369-77.Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives. To Reference
Ref 19Bioorg. Med. Chem. Lett. 7(3):297-302 (1997) To Reference
Ref 20Bioorg Med Chem. 2009 Oct 15;17(20):7197-208. Epub 2009 Sep 2.PET-compatible endothelin receptor radioligands: synthesis and first in vitro and in vivo studies. To Reference
Ref 21Bioorg. Med. Chem. Lett. 4(4):567-572 (1994) To Reference
Ref 22J Nat Prod. 2002 Jan;65(1):7-10.New chlorinated diphenyl ethers from an Aspergillus species. To Reference
Ref 23J Nat Prod. 2009 Dec;72(12):2172-6.5-OHKF and NorKA, depsipeptides from a Hawaiian collection of Bryopsis pennata: binding properties for NorKA to the human neuropeptide Y Y1 receptor. To Reference
Ref 24Endothelin in heart failure: a promising therapeutic target? Heart. 1997 Feb;77(2):93-4. To Reference
Ref 25The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system. Expert Opin Investig Drugs. 2002 Nov;11(11):1537-52. To Reference
Ref 26Human optic nerve head astrocytes as a target for endothelin-1. Invest Ophthalmol Vis Sci. 2002 Aug;43(8):2704-13. To Reference
Ref 27Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin. Biochem Pharmacol. 2002 Aug 1;64(3):497-505. To Reference
Ref 28Discovery and development of an endothelin A receptor-selective antagonist PD 156707. Pharm Biotechnol. 1998;11:81-112. To Reference
Ref 29Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm. Neurosurgery. 1998 Dec;43(6):1409-17; discussion 1417-8. To Reference



 

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