| Version |
2.5 |
| Creation Date |
2005-06-13 13:24:05 |
| Update Date |
2009-02-19 16:03:42 |
| Primary Accession Number |
DB00559 |
| Secondary Accession Number |
|
| Name |
Bosentan |
| Drug Type |
- Approved
- Investigational
- Small Molecule
|
| Description |
Bosentan is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer®. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure. |
| Synonyms |
- Bosentan hydrate
- bosentan
|
| Brand Names |
- Tracleer
|
| Brand Mixtures |
Not Available |
| Chemical IUPAC Name |
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]benzenesulfonamide |
| Chemical Formula |
C27H29N5O6S |
| Chemical Structure |
 |
| CAS Registry Number |
147536-97-8 |
| InChI Identifier |
InChI=1/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32)/f/h32H |
| InChI Key |
GJPICJJJRGTNOD-OKPOJWAQCQ |
| KEGG Drug |
D01227  |
| KEGG Compound |
Not Available |
| PubChem Compound |
104865  |
| PubChem Substance |
682323  |
| ChEBI ID |
Not Available |
| PharmGKB ID |
PA10034  |
| HET ID |
Not Available |
| GenBank ID |
Not Available |
| Drug ID Number [DIN] |
02244982  |
| RxList Link |
http://www.rxlist.com/cgi/generic3/tracleer.htm  |
| PDRhealth Link |
Not Available |
| Wikipedia Link |
http://en.wikipedia.org/wiki/Bosentan  |
| FDA Label |
|
| Material Safety Data Sheet (MSDS) |
Not Available |
| Synthesis Reference |
Not Available |
| Average Molecular Weight |
551.6140 |
| Monoisotopic Molecular Weight |
551.1839 |
| State |
Solid |
| Melting Point |
Not Available |
| Experimental Water Solubility |
Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).
Source: PhysProp
|
| Predicted Water Solubility |
9.04e-03 mg/mL
Calculated using ALOGPS
|
| Experimental LogP/Hydrophobicity |
3.7
Source: PhysProp
|
| Predicted LogP |
4.18
Calculated using ALOGPS
|
| Experimental LogS |
Not Available |
| Predicted LogS |
-4.79
Calculated using ALOGPS
|
| Experimental Caco2 Permeability |
-5.98 [ADME Research, USCD] |
| pKa/Isoelectric Point |
Not Available |
| Mass Spectrum |
Not Available
|
| MOL File |
Show | Download  |
| SDF File |
Show | Download  |
| PDB File |
Show | Download  |
| 2D Structure |
|
| 3D Structure |
|
| Experimental PDB ID |
Not Available |
| Isomeric SMILES |
COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)N=C(N=C1OCCO)C1=NC=CC=N1 |
| Canonical SMILES |
COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)N=C(N=C1OCCO)C1=NC=CC=N1 |
| Drug Category |
|
| ATC Codes |
|
| AHFS Codes |
|
| Indication |
Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). |
| Pharmacology |
Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. |
| Mechanism of Action |
Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. |
| Absorption |
Absolute bioavailability is approximately 50% and food does not affect absorption. |
| Toxicity |
Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. |
| Protein Binding |
Greater than 98% to plasma proteins, mainly albumin. |
| Biotransformation |
Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. |
| Half Life |
Terminal elimination half-life is about 5 hours in healthy adult subjects. |
| Dosage Forms |
| Form |
Route |
| Tablet |
Oral |
| Tablet |
Oral |
|
| Patient Information |
Show  |
| Contraindications |
Show  |
| Interactions |
Show  |
| Drug Interactions |
| Drug |
Interaction |
| Acenocoumarol |
Increases the anticoagulant effect |
| Anisindione |
Increases the anticoagulant effect |
| Atorvastatin |
Bosentan could decrease atorvastatin effect |
| Cerivastatin |
Bosentan could decrease the statin effect |
| Cyclosporine |
Cyclosporine increases the effect and toxicity of bosentan |
| Dicumarol |
Increase the anticoagulant effect |
| Ethinyl Estradiol |
Decreases the effect of contraceptive |
| Glibenclamide |
Increased risk of hepatic toxicity |
| Itraconazole |
This imidazole increases the effect and toxicity of bosentan |
| Ketoconazole |
This imidazole increases the effect and toxicity of bosentan |
| Lovastatin |
Bosentan could decrease the statin effect |
| Medroxyprogesterone |
Decreases the effect of contraceptive |
| Mestranol |
Decreases the effect of contraceptive |
| Norethindrone |
Decreases the effect of contraceptive |
| Simvastatin |
Bosentan could decrease the statin effect |
| Voriconazole |
This imidazole increases the effect and toxicity of bosentan |
| Warfarin |
Increases the anticoagulant effect |
|
| Food Interactions |
- Take without regard to meals.
|
| Pathways |
Not Available
|
| General References |
- Wikipedia

- RxList

|
| Organisms Affected |
|
| Phase 1 Metabolizing Enzymes |
- Cytochrome P450 3A4 (CYP3A4)
- Cytochrome P450 2C9 (CYP2C9)
|
| Targets |
- Endothelin B receptor
- Endothelin-1 receptor
- Bile salt export pump
|
|
Drug Target 1
[top]
|
| Target 1 ID |
49 |
| Target 1 Name |
Endothelin B receptor |
| Target 1 Synonyms |
- ET-B
- Endothelin B receptor precursor
- Endothelin receptor Non- selective type
|
| Target 1 Gene Name |
EDNRB |
| Target 1 Protein Sequence |
>Endothelin B receptor precursor
MQPPPSLCGRALVALVLACGLSRIWGEERGFPPDRATPLLQTAEIMTPPTKTLWPKGSNA
SLARSLAPAEVPKGDRTAGSPPRTISPPPCQGPIEIKETFKYINTVVSCLVFVLGIIGNS
TLLRIIYKNKCMRNGPNILIASLALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFI
QKASVGITVLSLCALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIWVVSVVLAVPEAIGF
DIITMDYKGSYLRICLLHPVQKTAFMQFYKTAKDWWLFSFYFCLPLAITAFFYTLMTCEM
LRKKSGMQIALNDHLKQRREVAKTVFCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCEL
LSFLLVLDYIGINMASLNSCINPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQSC
LKFKANDHGYDNFRSSNKYSSS
|
| Target 1 Number of Residues |
449 |
| Target 1 Molecular Weight |
49644 |
| Target 1 Theoretical pI |
9.05 |
| Target 1 GO Classification |
|
Function
|
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
peptide receptor activity, G-protein coupled
endothelin receptor activity |
|
Process
|
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway |
|
Component
|
cell
membrane
intrinsic to membrane
integral to membrane |
|
| Target 1 General Function |
Involved in endothelin receptor activity |
| Target 1 Specific Function |
Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system |
| Target 1 Pathways |
Not Available
|
| Target 1 Reactions |
Not Available |
| Target 1 Pfam Domain Function |
|
| Target 1 Signals |
|
| Target 1 Transmembrane Regions |
- 102-126
- 138-163
- 176-197
- 219-243
- 272-296
- 325-350
- 363-389
|
| Target 1 Essentiality |
Non-Essential |
| Target 1 GenBank ID Protein |
182276  |
| Target 1 UniProtKB/Swiss-Prot ID |
P24530  |
| Target 1 UniProtKB/Swiss-Prot Entry Name |
EDNRB_HUMAN  |
| Target 1 PDB ID |
Not Available |
| Target 1 Cellular Location |
- Membrane
- multi-pass membrane protein
|
| Target 1 Gene Sequence |
>1329 bp
ATGCAGCCGCCTCCAAGTCTGTGCGGACGCGCCCTGGTTGCGCTGGTTCTTGCCTGCGGC
CTGTCGCGGATCTGGGGAGAGGAGAGAGGCTTCCCGCCTGACAGGGCCACTCCGCTTTTG
CAAACCGCAGAGATAATGACGCCACCCACTAAGACCTTATGGCCCAAGGGTTCCAACGCC
AGTCTGGCGCGGTCGTTGGCACCTGCGGAGGTGCCTAAAGGAGACAGGACGGCAGGATCT
CCGCCACGCACCATCTCCCCTCCCCCGTGCCAAGGACCCATCGAGATCAAGGAGACTTTC
AAATACATCAACACGGTTGTGTCCTGCCTTGTGTTCGTGCTGGGGATCATCGGGAACTCC
ACACTTCTGAGAATTATCTACAAGAACAAGTGCATGCGAAACGGTCCCAATATCTTGATC
GCCAGCTTGGCTCTGGGAGACCTGCTGCACATCGTCATTGACATCCCTATCAATGTCTAC
AAGCTGCTGGCAGAGGACTGGCCATTTGGAGCTGAGATGTGTAAGCTGGTGCCTTTCATA
CAGAAAGCCTCCGTGGGAATCACTGTGCTGAGTCTATGTGCTCTGAGTATTGACAGATAT
CGAGCTGTTGCTTCTTGGAGTAGAATTAAAGGAATTGGGGTTCCAAAATGGACAGCAGTA
GAAATTGTTTTGATTTGGGTGGTCTCTGTGGTTCTGGCTGTCCCTGAAGCCATAGGTTTT
GATATAATTACGATGGACTACAAAGGAAGTTATCTGCGAATCTGCTTGCTTCATCCCGTT
CAGAAGACAGCTTTCATGCAGTTTTACAAGACAGCAAAAGATTGGTGGCTGTTCAGTTTC
TATTTCTGCTTGCCATTGGCCATCACTGCATTTTTTTATACACTAATGACCTGTGAAATG
TTGAGAAAGAAAAGTGGCATGCAGATTGCTTTAAATGATCACCTAAAGCAGAGACGGGAA
GTGGCCAAAACCGTCTTTTGCCTGGTCCTTGTCTTTGCCCTCTGCTGGCTTCCCCTTCAC
CTCAGCAGGATTCTGAAGCTCACTCTTTATAATCAGAATGATCCCAATAGATGTGAACTT
TTGAGCTTTCTGTTGGTATTGGACTATATTGGTATCAACATGGCTTCACTGAATTCCTGC
ATTAACCCAATTGCTCTGTATTTGGTGAGCAAAAGATTCAAAAACTGCTTTAAGTCATGC
TTATGCTGCTGGTGCCAGTCATTTGAAGAAAAACAGTCCTTGGAGGAAAAGCAGTCGTGC
TTAAAGTTCAAAGCTAATGATCACGGATATGACAACTTCCGTTCCAGTAATAAATACAGC
TCATCTTGA
|
| Target 1 GenBank Gene ID |
|
| Target 1 GeneCard ID |
EDNRB  |
| Target 1 GenAtlas ID |
EDNRB  |
| Target 1 HGNC ID |
HGNC:3180  |
| Target 1 Chromosome Location |
13 |
| Target 1 Locus |
13q22 |
| Target 1 SNPs |
SNPJam Report  |
| Target 1 General References |
- Tsutsumi M, Liang G, Jones PA: Novel endothelin B receptor transcripts with the potential of generating a new receptor. Gene. 1999 Mar 4;228(1-2):43-9. [PubMed
]
- Fuchs S, Amiel J, Claudel S, Lyonnet S, Corvol P, Pinet F: Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease: evidence for selective loss of Gi coupling. Mol Med. 2001 Feb;7(2):115-24. [PubMed
]
- Verheij JB, Kunze J, Osinga J, van Essen AJ, Hofstra RM: ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. Am J Med Genet. 2002 Mar 15;108(3):223-5. [PubMed
]
- Pingault V, Girard M, Bondurand N, Dorkins H, Van Maldergem L, Mowat D, Shimotake T, Verma I, Baumann C, Goossens M: SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism. Hum Genet. 2002 Aug;111(2):198-206. Epub 2002 Jul 6. [PubMed
]
- Haendler B, Hechler U, Schleuning WD: Molecular cloning of human endothelin (ET) receptors ETA and ETB. J Cardiovasc Pharmacol. 1992;20 Suppl 12:S1-4. [PubMed
]
- Arai H, Nakao K, Hosoda K, Ogawa Y, Nakagawa O, Komatsu Y, Imura H: [Molecular cloning of human endothelin receptors and their expression in vascular endothelial cells and smooth muscle cells] Jpn Circ J. 1992;56 Suppl 5:1303-7. [PubMed
]
- Ogawa Y, Nakao K, Arai H, Nakagawa O, Hosoda K, Suga S, Nakanishi S, Imura H: Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem Biophys Res Commun. 1991 Jul 15;178(1):248-55. [PubMed
]
- Nakamuta M, Takayanagi R, Sakai Y, Sakamoto S, Hagiwara H, Mizuno T, Saito Y, Hirose S, Yamamoto M, Nawata H: Cloning and sequence analysis of a cDNA encoding human non-selective type of endothelin receptor. Biochem Biophys Res Commun. 1991 May 31;177(1):34-9. [PubMed
]
- Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T: Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun. 1991 Jul 31;178(2):656-63. [PubMed
]
- Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravart A: A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell. 1994 Dec 30;79(7):1257-66. [PubMed
]
- 8429023 Arai H, Nakao K, Takaya K, Hosoda K, Ogawa Y, Nakanishi S, Imura H: The human endothelin-B receptor gene. Structural organization and chromosomal assignment. J Biol Chem. 1993 Feb 15;268(5):3463-70.
- 8440682 Elshourbagy NA, Korman DR, Wu HL, Sylvester DR, Lee JA, Nuthalaganti P, Bergsma DJ, Kumar CS, Nambi P: Molecular characterization and regulation of the human endothelin receptors. J Biol Chem. 1993 Feb 25;268(6):3873-9.
- 8630503 Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet. 1996 Apr;12(4):445-7.
- 8634719 Attie T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S: Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995 Dec;4(12):2407-9.
- 8852659 Auricchio A, Casari G, Staiano A, Ballabio A: Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet. 1996 Mar;5(3):351-4.
- 8852660 Amiel J, Attie T, Jan D, Pelet A, Edery P, Bidaud C, Lacombe D, Tam P, Simeoni J, Flori E, Nihoul-Fekete C, Munnich A, Lyonnet S: Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):355-7.
- 9261180 Okamoto Y, Ninomiya H, Tanioka M, Sakamoto A, Miwa S, Masaki T: Palmitoylation of human endothelinB. Its critical role in G protein coupling and a differential requirement for the cytoplasmic tail by G protein subtypes. J Biol Chem. 1997 Aug 22;272(34):21589-96.
- 9284755 Bourgeois C, Robert B, Rebourcet R, Mondon F, Mignot TM, Duc-Goiran P, Ferre F: Endothelin-1 and ETA receptor expression in vascular smooth muscle cells from human placenta: a new ETA receptor messenger ribonucleic acid is generated by alternative splicing of exon 3. J Clin Endocrinol Metab. 1997 Sep;82(9):3116-23.
- 9359036 Hofstra RM, Osinga J, Buys CH: Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype. Eur J Hum Genet. 1997 Jul-Aug;5(4):180-5.
- 9760196 Svensson PJ, Anvret M, Molander ML, Nordenskjold A: Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B). Hum Genet. 1998 Aug;103(2):145-8.
|
| Target 1 Drug References |
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed
]
- Said SA, Ammar el SM, Suddek GM: Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res. 2005 Feb;51(2):107-15. [PubMed
]
- Gupta SK, Saxena A, Singh U, Arya DS: Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2005 Jul;275(1-2):67-74. [PubMed
]
- Richard V, Kaeffer N, Hogie M, Tron C, Blanc T, Thuillez C: Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. Br J Pharmacol. 1994 Nov;113(3):869-76. [PubMed
]
- Gardiner SM, Kemp PA, March JE, Bennett T: Effects of bosentan (Ro 47-0203), an ETA-, ETB-receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats. Br J Pharmacol. 1994 Jul;112(3):823-30. [PubMed
]
- Marano G, Palazzesi S, Bernucci P, Grigioni M, Formigari R, Ballerini L: ET(A)/ET(B) receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits. Life Sci. 1998;63(18):PL259-66. [PubMed
]
|
|
Drug Target 2
[top]
|
| Target 2 ID |
578 |
| Target 2 Name |
Endothelin-1 receptor |
| Target 2 Synonyms |
- ET-A
- ETA-R
- Endothelin A receptor
- Endothelin-1 receptor precursor
- hET- AR
|
| Target 2 Gene Name |
EDNRA |
| Target 2 Protein Sequence |
>Endothelin-1 receptor precursor
METLCLRASFWLALVGCVISDNPERYSTNLSNHVDDFTTFRGTELSFLVTTHQPTNLVLP
SNGSMHNYCPQQTKITSAFKYINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIA
SLALGDLIYVVIDLPINVFKLLAGRWPFDHNDFGVFLCKLFPFLQKSSVGITVLNLCALS
VDRYRAVASWSRVQGIGIPLVTAIEIVSIWILSFILAIPEAIGFVMVPFEYRGEQHKTCM
LNATSKFMEFYQDVKDWWLFGFYFCMPLVCTAIFYTLMTCEMLNRRNGSLRIALSEHLKQ
RREVAKTVFCLVVIFALCWFPLHLSRILKKTVYNEMDKNRCELLSFLLLMDYIGINLATM
NSCINPIALYFVSKKFKNCFQSCLCCCCYQSKSLMTSVPMNGTSIQWKNHDQNNHNTDRS
SHKDSMN
|
| Target 2 Number of Residues |
434 |
| Target 2 Molecular Weight |
48723 |
| Target 2 Theoretical pI |
8.41 |
| Target 2 GO Classification |
|
Function
|
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
peptide receptor activity, G-protein coupled
endothelin receptor activity |
|
Process
|
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway |
|
Component
|
cell
membrane
intrinsic to membrane
integral to membrane |
|
| Target 2 General Function |
Involved in endothelin receptor activity |
| Target 2 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:ET1 > ET2 >> ET3 |
| Target 2 Pathways |
Not Available
|
| Target 2 Reactions |
Not Available |
| Target 2 Pfam Domain Function |
|
| Target 2 Signals |
|
| Target 2 Transmembrane Regions |
- 81-102
- 113-132
- 160-181
- 206-229
- 257-278
- 307-328
- 348-372
|
| Target 2 Essentiality |
Non-Essential |
| Target 2 GenBank ID Protein |
238636  |
| Target 2 UniProtKB/Swiss-Prot ID |
P25101  |
| Target 2 UniProtKB/Swiss-Prot Entry Name |
EDNRA_HUMAN  |
| Target 2 PDB ID |
Not Available |
| Target 2 Cellular Location |
- Membrane
- multi-pass membrane protein
|
| Target 2 Gene Sequence |
>1284 bp
ATGGAAACCCTTTGCCTCAGGGCATCCTTTTGGCTGGCACTGGTTGGATGTGTAATCAGT
GATAATCCTGAGAGATACAGCACAAATCTAAGCAATCATGTGGATGATTTCACCACTTTT
CGTGGCACAGAGCTCAGCTTCCTGGTTACCACTCATCAACCCACTAATTTGGTCCTACCC
AGCAATGGCTCAATGCACAACTATTGCCCACAGCAGACTAAAATTACTTCAGCTTTCAAA
TACATTAACACTGTGATATCTTGTACTATTTTCATCGTGGGAATGGTGGGGAATGCAACT
CTGCTCAGGATCATTTACCAGAACAAATGTATGAGGAATGGCCCCAACGCGCTGATAGCC
AGTCTTGCCCTTGGAGACCTTATCTATGTGGTCATTGATCTCCCTATCAATGTATTTAAG
CTGCTGGCTGGGCGCTGGCCTTTTGATCACAATGACTTTGGCGTATTTCTTTGCAAGCTG
TTCCCCTTTTTGCAGAAGTCCTCGGTGGGGATCACCGTCCTCAACCTCTGCGCTCTTAGT
GTTGACAGGTACAGAGCAGTTGCCTCCTGGAGTCGTGTTCAGGGAATTGGGATTCCTTTG
GTAACTGCCATTGAAATTGTCTCCATCTGGATCCTGTCCTTTATCCTGGCCATTCCTGAA
GCGATTGGCTTCGTCATGGTACCCTTTGAATATAGGGGTGAACAGCATAAAACCTGTATG
CTCAATGCCACATCAAAATTCATGGAGTTCTACCAAGATGTAAAGGACTGGTGGCTCTTC
GGGTTCTATTTCTGTATGCCCTTGGTGTGCACTGCGATCTTCTACACCCTCATGACTTGT
GAGATGTTGAACAGAAGGAATGGCAGCTTGAGAATTGCCCTCAGTGAACATCTTAAGCAG
CGTCGAGAAGTGGCAAAAACAGTTTTCTGCTTGGTTGTAATTTTTGCTCTTTGCTGGTTC
CCTCTTCATTTAAGCCGTATATTGAAGAAAACTGTGTATAACGAGATGGACAAGAACCGA
TGTGAATTACTTAGTTTCTTACTGCTCATGGATTACATCGGTATTAACTTGGCAACCATG
AATTCATGTATAAACCCCATAGCTCTGTATTTTGTGAGCAAGAAATTTAAAAATTGTTTC
CAGTCATGCCTCTGCTGCTGCTGTTACCAGTCCAAAAGTCTGATGACCTCGGTCCCCATG
AACGGAACAAGCATCCAGTGGAAGAACCACGATCAAAACAACCACAACACAGACCGGAGC
AGCCATAAGGACAGCATGAACTGA
|
| Target 2 GenBank Gene ID |
|
| Target 2 GeneCard ID |
EDNRA  |
| Target 2 GenAtlas ID |
EDNRA  |
| Target 2 HGNC ID |
HGNC:3179  |
| Target 2 Chromosome Location |
4 |
| Target 2 Locus |
4q31.23 |
| Target 2 SNPs |
SNPJam Report  |
| Target 2 General References |
- Lee HJ, Chun M, Kandror KV: Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling. J Biol Chem. 2001 May 18;276(20):16597-600. Epub 2001 Mar 21. [PubMed
]
- Arai H, Nakao K, Hosoda K, Ogawa Y, Nakagawa O, Komatsu Y, Imura H: [Molecular cloning of human endothelin receptors and their expression in vascular endothelial cells and smooth muscle cells] Jpn Circ J. 1992;56 Suppl 5:1303-7. [PubMed
]
- Hosoda K, Nakao K, Tamura N, Arai H, Ogawa Y, Suga S, Nakanishi S, Imura H: Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelin-A receptor. J Biol Chem. 1992 Sep 15;267(26):18797-804. [PubMed
]
- Hayzer DJ, Rose PM, Lynch JS, Webb ML, Kienzle BK, Liu EC, Bogosian EA, Brinson E, Runge MS: Cloning and expression of a human endothelin receptor: subtype A. Am J Med Sci. 1992 Oct;304(4):231-8. [PubMed
]
- Hosoda K, Nakao K, Hiroshi-Arai, Suga S, Ogawa Y, Mukoyama M, Shirakami G, Saito Y, Nakanishi S, Imura H: Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett. 1991 Aug 5;287(1-2):23-6. [PubMed
]
- Cyr C, Huebner K, Druck T, Kris R: Cloning and chromosomal localization of a human endothelin ETA receptor. Biochem Biophys Res Commun. 1991 Nov 27;181(1):184-90. [PubMed
]
- Adachi M, Yang YY, Furuichi Y, Miyamoto C: Cloning and characterization of cDNA encoding human A-type endothelin receptor. Biochem Biophys Res Commun. 1991 Nov 14;180(3):1265-72. [PubMed
]
- Yang H, Tabuchi H, Furuichi Y, Miyamoto C: Molecular characterization of the 5'-flanking region of human genomic ETA gene. Biochem Biophys Res Commun. 1993 Jan 29;190(2):332-9. [PubMed
]
- Elshourbagy NA, Korman DR, Wu HL, Sylvester DR, Lee JA, Nuthalaganti P, Bergsma DJ, Kumar CS, Nambi P: Molecular characterization and regulation of the human endothelin receptors. J Biol Chem. 1993 Feb 25;268(6):3873-9. [PubMed
]
- Miyamoto Y, Yoshimasa T, Arai H, Takaya K, Ogawa Y, Itoh H, Nakao K: Alternative RNA splicing of the human endothelin-A receptor generates multiple transcripts. Biochem J. 1996 Feb 1;313 ( Pt 3):795-801. [PubMed
]
- 9284755 Bourgeois C, Robert B, Rebourcet R, Mondon F, Mignot TM, Duc-Goiran P, Ferre F: Endothelin-1 and ETA receptor expression in vascular smooth muscle cells from human placenta: a new ETA receptor messenger ribonucleic acid is generated by alternative splicing of exon 3. J Clin Endocrinol Metab. 1997 Sep;82(9):3116-23.
|
| Target 2 Drug References |
- Martin C, Held HD, Uhlig S: Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. [PubMed
]
- Kiowski W, Sutsch G, Oechslin E, Bertel O: Hemodynamic effects of bosentan in patients with chronic heart failure. Heart Fail Rev. 2001 Dec;6(4):325-34. [PubMed
]
- Kramp R, Fourmanoir P, Caron N: Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat. Am J Physiol Renal Physiol. 2001 Dec;281(6):F1132-40. [PubMed
]
- Albertini M, Lafortuna CL, Ciminaghi B, Mazzola S, Clement MG: Endothelin involvement in respiratory centre activity. Prostaglandins Leukot Essent Fatty Acids. 2001 Sep;65(3):157-63. [PubMed
]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed
]
- Sihvola RK, Pulkkinen VP, Koskinen PK, Lemstrom KB: Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. J Am Coll Cardiol. 2002 Feb 20;39(4):710-7. [PubMed
]
|
|
Drug Target 3
[top]
|
| Target 3 ID |
776 |
| Target 3 Name |
Bile salt export pump |
| Target 3 Synonyms |
- ATP-binding cassette sub-family B member 11
|
| Target 3 Gene Name |
ABCB11 |
| Target 3 Protein Sequence |
>Bile salt export pump
MSDSVILRSIKKFGEENDGFESDKSYNNDKKSRLQDEKKGDGVRVGFFQLFRFSSSTDIW
LMFVGSLCAFLHGIAQPGVLLIFGTMTDVFIDYDVELQELQIPGKACVNNTIVWTNSSLN
QNMTNGTRCGLLNIESEMIKFASYYAGIAVAVLITGYIQICFWVIAAARQIQKMRKFYFR
RIMRMEIGWFDCNSVGELNTRFSDDINKINDAIADQMALFIQRMTSTICGFLLGFFRGWK
LTLVIISVSPLIGIGAATIGLSVSKFTDYELKAYAKAGVVADEVISSMRTVAAFGGEKRE
VERYEKNLVFAQRWGIRKGIVMGFFTGFVWCLIFLCYAVAFWYGSTLVLDEGEYTPGTLV
QIFLSVIVGALNLGNASPCLEAFATGRAAATSIFETIDRKPIIDCMSEDGYKLDRIKGEI
EFHNVTFHYPSRPEVKILNDLNMVIKPGEMTALVGPSGAGKSTALQLIQRFYDPCEGMVT
VDGHDIRSLNIQWLRDQIGIVEQEPVLFSTTIAENIRYGREDATMEDIVQAAKEANAYNF
IMDLPQQFDTLVGEGGGQMSGGQKQRVAIARALIRNPKILLLDMATSALDNESEAMVQEV
LSKIQHGHTIISVAHRLSTVRAADTIIGFEHGTAVERGTHEELLERKGVYFTLVTLQSQG
NQALNEEDIKDATEDDMLARTFSRGSYQDSLRASIRQRSKSQLSYLVHEPPLAVVDHKST
YEEDRKDKDIPVQEEVEPAPVRRILKFSAPEWPYMLVGSVGAAVNGTVTPLYAFLFSQIL
GTFSIPDKEEQRSQINGVCLLFVAMGCVSLFTQFLQGYAFAKSGELLTKRLRKFGFRAML
GQDIAWFDDLRNSPGALTTRLATDASQVQGAAGSQIGMIVNSFTNVTVAMIIAFSFSWKL
SLVILCFFPFLALSGATQTRMLTGFASRDKQALEMVGQITNEALSNIRTVAGIGKERRFI
EALETELEKPFKTAIQKANIYGFCFAFAQCIMFIANSASYRYGGYLISNEGLHFSYVFRV
ISAVVLSATALGRAFSYTPSYAKAKISAARFFQLLDRQPPISVYNTAGEKWDNFQGKIDF
VDCKFTYPSRPDSQVLNGLSVSISPGQTLAFVGSSGCGKSTSIQLLERFYDPDQGKVMID
GHDSKKVNVQFLRSNIGIVSQEPVLFACSIMDNIKYGDNTKEIPMERVIAAAKQAQLHDF
VMSLPEKYETNVGSQGSQLSRGEKQRIAIARAIVRDPKILLLDEATSALDTESEKTVQVA
LDKAREGRTCIVIAHRLSTIQNADIIAVMAQGVVIEKGTHEELMAQKGAYYKLVTTGSPI
S
|
| Target 3 Number of Residues |
1343 |
| Target 3 Molecular Weight |
146395 |
| Target 3 Theoretical pI |
6.52 |
| Target 3 GO Classification |
|
Function
|
ATPase activity
hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances
ATPase activity, coupled to transmembrane movement of substances
purine nucleotide binding
adenyl nucleotide binding
ATP binding
catalytic activity
hydrolase activity
hydrolase activity, acting on acid anhydrides
hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides
pyrophosphatase activity
nucleoside-triphosphatase activity
binding
nucleotide binding |
|
Process
|
physiological process
cellular physiological process
transport |
|
Component
|
cell
membrane
intrinsic to membrane
integral to membrane |
|
| Target 3 General Function |
Defense mechanisms |
| Target 3 Specific Function |
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes |
| Target 3 Pathways |
Not Available
|
| Target 3 Reactions |
Not Available |
| Target 3 Pfam Domain Function |
|
| Target 3 Signals |
|
| Target 3 Transmembrane Regions |
- 63-83
- 148-168
- 216-236
- 241-261
- 320-340
- 354-374
- 756-776
- 795-815
- 870-890
- 891-911
- 980-1000
- 1012-1032
|
| Target 3 Essentiality |
Non-Essential |
| Target 3 GenBank ID Protein |
3873243  |
| Target 3 UniProtKB/Swiss-Prot ID |
O95342  |
| Target 3 UniProtKB/Swiss-Prot Entry Name |
ABCBB_HUMAN  |
| Target 3 PDB ID |
Not Available |
| Target 3 Cellular Location |
- Membrane
- multi-pass membrane protein
|
| Target 3 Gene Sequence |
>3966 bp
ATGTCTGACTCAGTAATTCTTCGAAGTATAAAGAAATTTGGAGAGGAGAATGATGGTTTT
GAGTCAGATAAATCATATAATAATGATAAGAAATCAAGGTTACAAGATGAGAAGAAAGGT
GATGGCGTTAGAGTTGGCTTCTTTCAATTGTTTCGGTTTTCTTCATCAACTGACATTTGG
CTGATGTTTGTGGGAAGTTTGTGTGCATTTCTCCATGGAATAGCCCAGCCAGGCGTGCTA
CTCATTTTTGGCACAATGACAGATGTTTTTATTGACTACGACGTTGAGTTACAAGAACTC
CAGATTCCAGGAAAAGCATGTGTGAATAACACCATTGTATGGACTAACAGTTCCCTCAAC
CAGAACATGACAAATGGAACACGTTGTGGGTTGCTGAACATCGAGAGCGAAATGATCAAA
TTTGCCAGTTACTATGCTGGAATTGCTGTCGCAGTACTTATCACAGGATATATTCAAATA
TGCTTTTGGGTCATTGCCGCAGCTCGTCAGATACAGAAAATGAGAAAATTTTACTTTAGG
AGAATAATGAGAATGGAAATAGGGTGGTTTGACTGCAATTCAGTGGGGGAGCTGAATACA
AGATTCTCTGATGATATTAATAAAATCAATGATGCCATAGCTGACCAAATGGCCCTTTTC
ATTCAGCGCATGACCTCGACCATCTGTGGTTTCCTGTTGGGATTTTTCAGGGGTTGGAAA
CTGACCTTGGTTATTATTTCTGTCAGCCCTCTCATTGGGATTGGAGCAGCCACCATTGGT
CTGAGTGTGTCCAAGTTTACGGACTATGAGCTGAAGGCCTATGCCAAAGCAGGGGTGGTG
GCTGATGAAGTCATTTCATCAATGAGAACAGTGGCTGCTTTTGGTGGTGAGAAAAGAGAG
GTTGAAAGGTATGAGAAAAATCTTGTGTTCGCCCAGCGTTGGGGAATTAGAAAAGGAATA
GTGATGGGATTCTTTACTGGATTCGTGTGGTGTCTCATCTTTTTGTGTTATGCAGTGGCC
TTCTGGTACGGCTCCACACTTGTCCTGGATGAAGGAGAATATACACCAGGAACCCTTGTC
CAGATTTTCCTCAGTGTCATAGTAGGAGCTTTAAATCTTGGCAATGCCTCTCCTTGTTTG
GAAGCCTTTGCAACTGGACGTGCAGCAGCCACCAGCATTTTTGAGACAATAGACAGGAAA
CCCATCATTGACTGCATGTCAGAAGATGGTTACAAGTTGGATCGAATCAAGGGTGAAATT
GAATTCCATAATGTGACCTTCCATTATCCTTCCAGACCAGAGGTGAAGATTCTAAATGAC
CTCAACATGGTCATTAAACCAGGGGAAATGACAGCTCTGGTAGGACCCAGTGGAGCTGGA
AAAAGTACAGCACTGCAACTCATTCAGCGATTCTATGACCCCTGTGAAGGAATGGTGACC
GTGGATGGCCATGACATTCGCTCTCTTAACATTCAGTGGCTTAGAGATCAGATTGGGATA
GTGGAGCAAGAGCCAGTTCTGTTCTCTACCACCATTGCAGAAAATATTCGCTATGGCAGA
GAAGATGCAACAATGGAAGACATAGTCCAAGCTGCCAAGGAGGCCAATGCCTACAACTTC
ATCATGGACCTGCCACAGCAATTTGACACCCTTGTTGGAGAAGGAGGAGGCCAGATGAGT
GGTGGCCAGAAACAAAGGGTAGCTATCGCCAGAGCCCTCATCCGAAATCCCAAGATTCTG
CTTTTGGACATGGCCACCTCAGCTCTGGACAATGAGAGTGAAGCCATGGTGCAAGAAGTG
CTGAGTAAGATTCAGCATGGGCACACAATCATTTCAGTTGCTCATCGCTTGTCTACGGTC
AGAGCTGCAGATACCATCATTGGTTTTGAACATGGCACTGCAGTGGAAAGAGGGACCCAT
GAAGAATTACTGGAAAGGAAAGGTGTTTACTTCACTCTAGTGACTTTGCAAAGCCAGGGA
AATCAAGCTCTTAATGAAGAGGACATAAAGGATGCAACTGAAGATGACATGCTTGCGAGG
ACCTTTAGCAGAGGGAGCTACCAGGATAGTTTAAGGGCTTCCATCCGGCAACGCTCCAAG
TCTCAGCTTTCTTACCTGGTGCACGAACCTCCATTAGCTGTTGTAGATCATAAGTCTACC
TATGAAGAAGATAGAAAGGACAAGGACATTCCTGTGCAGGAAGAAGTTGAACCTGCCCCA
GTTAGGAGGATTCTGAAATTCAGTGCTCCAGAATGGCCCTACATGCTGGTAGGGTCTGTG
GGTGCAGCTGTGAACGGGACAGTCACACCCTTGTATGCCTTTTTATTCAGCCAGATTCTT
GGGACTTTTTCAATTCCTGATAAAGAGGAACAAAGGTCACAGATCAATGGTGTGTGCCTA
CTTTTTGTAGCAATGGGCTGTGTATCTCTTTTCACCCAATTTCTACAGGGATATGCCTTT
GCTAAATCTGGGGAGCTCCTAACAAAAAGGCTACGTAAATTTGGTTTCAGGGCAATGCTG
GGGCAAGATATTGCCTGGTTTGATGACCTCAGAAATAGCCCTGGAGCATTGACAACAAGA
CTTGCTACAGATGCTTCCCAAGTTCAAGGGGCTGCCGGCTCTCAGATCGGGATGATAGTC
AATTCCTTCACTAACGTCACTGTGGCCATGATCATTGCCTTCTCCTTTAGCTGGAAGCTG
AGCCTGGTCATCTTGTGCTTCTTCCCCTTCTTGGCTTTATCAGGAGCCACACAGACCAGG
ATGTTGACAGGATTTGCCTCTCGAGATAAGCAGGCCCTGGAGATGGTGGGACAGATTACA
AATGAAGCCCTCAGTAACATCCGCACTGTTGCTGGAATTGGAAAGGAGAGGCGGTTCATT
GAAGCACTTGAGACTGAGCTGGAGAAGCCCTTCAAGACAGCCATTCAGAAAGCCAATATT
TACGGATTCTGCTTTGCCTTTGCCCAGTGCATCATGTTTATTGCGAATTCTGCTTCCTAC
AGATATGGAGGTTACTTAATCTCCAATGAGGGGCTCCATTTCAGCTATGTGTTCAGGGTG
ATCTCTGCAGTTGTACTGAGTGCAACAGCTCTTGGAAGAGCCTTCTCTTACACCCCAAGT
TATGCAAAAGCTAAAATATCAGCTGCACGCTTTTTTCAACTGCTGGACCGACAACCCCCA
ATCAGTGTATACAATACTGCAGGTGAAAAATGGGACAACTTCCAGGGGAAGATTGATTTT
GTTGATTGTAAATTTACATATCCTTCTCGACCTGACTCGCAAGTTCTGAATGGTCTCTCA
GTGTCGATTAGTCCAGGGCAGACACTGGCGTTTGTTGGGAGCAGTGGATGTGGCAAAAGC
ACTAGCATTCAGCTGTTGGAACGTTTCTATGATCCTGATCAAGGGAAGGTGATGATAGAT
GGTCATGACAGCAAAAAAGTAAATGTCCAGTTCCTCCGCTCAAACATTGGAATTGTTTCC
CAGGAACCAGTGTTGTTTGCCTGTAGCATAATGGACAATATCAAGTATGGAGACAACACC
AAAGAAATTCCCATGGAAAGAGTCATAGCAGCTGCAAAACAGGCTCAGCTGCATGATTTT
GTCATGTCACTCCCAGAGAAATATGAAACTAACGTTGGGTCCCAGGGGTCTCAACTCTCT
AGAGGGGAGAAACAACGCATTGCTATTGCTCGGGCCATTGTACGAGATCCTAAAATCTTG
CTACTAGATGAAGCCACTTCTGCCTTAGACACAGAAAGTGAAAAGACGGTGCAGGTTGCT
CTAGACAAAGCCAGAGAGGGTCGGACCTGCATTGTCATTGCCCATCGCTTGTCCACCATC
CAGAACGCGGATATCATTGCTGTCATGGCACAGGGGGTGGTGATTGAAAAGGGGACCCAT
GAAGAACTGATGGCCCAAAAAGGAGCCTACTACAAACTAGTCACCACTGGATCCCCCATC
AGTTGA
|
| Target 3 GenBank Gene ID |
|
| Target 3 GeneCard ID |
ABCB11  |
| Target 3 GenAtlas ID |
ABCB11  |
| Target 3 HGNC ID |
HGNC:42  |
| Target 3 Chromosome Location |
2 |
| Target 3 Locus |
2q24 |
| Target 3 SNPs |
SNPJam Report  |
| Target 3 General References |
- Chen HL, Chang PS, Hsu HC, Ni YH, Hsu HY, Lee JH, Jeng YM, Shau WY, Chang MH: FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels. J Pediatr. 2002 Jan;140(1):119-24. [PubMed
]
- Saito S, Iida A, Sekine A, Miura Y, Ogawa C, Kawauchi S, Higuchi S, Nakamura Y: Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population. J Hum Genet. 2002;47(1):38-50. [PubMed
]
- Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ: A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998 Nov;20(3):233-8. [PubMed
]
|
| Target 3 Drug References |
- Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ: The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001 Apr;69(4):223-31. [PubMed
]
- Kemp DC, Brouwer KL: Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Toxicol In Vitro. 2004 Dec;18(6):869-77. [PubMed
]
- Kemp DC, Zamek-Gliszczynski MJ, Brouwer KL: Xenobiotics inhibit hepatic uptake and biliary excretion of taurocholate in rat hepatocytes. Toxicol Sci. 2005 Feb;83(2):207-14. Epub 2004 Oct 27. [PubMed
]
- Mano Y, Usui T, Kamimura H: Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos. 2007 Jan;28(1):13-8. [PubMed
]
|