Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT3ZTGU)

• DTT Name: Endothelin B receptor (EDNRB)
• Synonyms: Endothelin receptor type B; Endothelin receptor Non-selective type; Endothelin receptor B; ETRB; ET-BR; ET-B
• Gene Name: EDNRB
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: EDNRB_HUMAN
• TTD ID: T92828
• Sequence:
  MQPPPSLCGRALVALVLACGLSRIWGEERGFPPDRATPLLQTAEIMTPPTKTLWPKGSNA
  SLARSLAPAEVPKGDRTAGSPPRTISPPPCQGPIEIKETFKYINTVVSCLVFVLGIIGNS
  TLLRIIYKNKCMRNGPNILIASLALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFI
  QKASVGITVLSLCALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIWVVSVVLAVPEAIGF
  DIITMDYKGSYLRICLLHPVQKTAFMQFYKTAKDWWLFSFYFCLPLAITAFFYTLMTCEM
  LRKKSGMQIALNDHLKQRREVAKTVFCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCEL
  LSFLLVLDYIGINMASLNSCINPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQSC
  LKFKANDHGYDNFRSSNKYSSS
• Function: Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Non-specific receptor for endothelin 1, 2, and 3.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  Melanogenesis (hsa04916)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bosentan	DMIOGBU	Pulmonary arterial hypertension	BB01.0	Approved	[2]
Macitentan	DMP79A1	Cardiovascular disease	BA00-BE2Z	Approved	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BQ788	DM6KRLW	Acute kidney injury	GB60	Phase 3	[3]
PD-145065	DMWVBTQ	Hypertension	BA00-BA04	Phase 2	[4]
SPI-1620	DMNPRMC	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
ENB003	DMK2B3S	Melanoma	2C30	Phase 1/2	[6]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ENRASENTAN	DM05F1Z	Pulmonary arterial hypertension	BB01.0	Discontinued in Phase 2	[7]
J-104132	DM5E6MK	Pulmonary arterial hypertension	BB01.0	Discontinued in Phase 2	[8]
SB-209670	DMJYW80	Arrhythmia	BC9Z	Discontinued in Phase 2	[9]
IRL-2500	DMH6K7N	N. A.	N. A.	Terminated	[10]
PD142893	DMFA27N	N. A.	N. A.	Terminated	[11]
RES-701-1	DM1XYJU	N. A.	N. A.	Terminated	[12]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ET-1	DMA85ND	N. A.	N. A.	Phase 0	[10]

19 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
A192621	DMV8AH6	Discovery agent	N.A.	Investigative	[13]
Ac-bhg-F-N-Y-Y-W	DM1KDJV	Discovery agent	N.A.	Investigative	[14]
Ac-w-F-F-N-Y-Y-W	DMP89K4	Discovery agent	N.A.	Investigative	[14]
Bhg-F-N-Y-Y-W	DMVH4LK	Discovery agent	N.A.	Investigative	[14]
BQ 3020	DMQBRSM	Discovery agent	N.A.	Investigative	[15]
ENDG-4010	DMUCZPJ	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
Endothelin-3	DM0DM6X	Discovery agent	N.A.	Investigative	[17]
IRL-1722	DMMGQZ8	Discovery agent	N.A.	Investigative	[10]
IRL-1841	DML0S7V	Discovery agent	N.A.	Investigative	[10]
Linear peptide of RES-701-1	DMD3AJH	Discovery agent	N.A.	Investigative	[12]
LU302872	DM7F3SE	Discovery agent	N.A.	Investigative	[18]
PD-163140	DMBZ09U	Discovery agent	N.A.	Investigative	[19]
RES-701-1-C-terminal analogue	DMQEBKF	Discovery agent	N.A.	Investigative	[20]
Ro 46-8443	DMXMSYB	Discovery agent	N.A.	Investigative	[16]
Sarafotoxin 6C	DM0RDC4	Discovery agent	N.A.	Investigative	[11]
Trp-Ile-Ile-Asp-Leu-Hisc(Cys-Ser-Val-Tyr-Phe-Cys)	DM48QTG	Discovery agent	N.A.	Investigative	[21]
Trp-Ile-Ile-Asp-Leu-Hisc(Cys-Val-Tyr-Phe-Cys)	DMOZX8M	Discovery agent	N.A.	Investigative	[21]
W-F-F-N--Y-Y-W	DMAXOIS	Discovery agent	N.A.	Investigative	[14]
[125I]IRL1620	DMVEHI7	Discovery agent	N.A.	Investigative	[16]

References

• [1] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury-induced reactive astrocytes in rat brain. Glia. 1999 May;26(3):268-71.
• [4] Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065. Br J Pharmacol. 1994 May;112(1):207-13.
• [5] Clinical pipeline report, company report or official report of Spectrum Phamaceuticals (2009).
• [6] ClinicalTrials.gov (NCT04205227) A Phase 1/2A Trial of ENB 003 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors. U.S.National Institutes of Health.
• [7] Enrasentan, an antagonist of endothelin receptors. Cardiovasc Drug Rev. 2003 Spring;21(1):1-16.
• [8] Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist. J Pharmacol Exp Ther. 1999 Jun;289(3):1262-70.
• [9] Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. Br J Pharmacol. 1996 May;118(1):198-204.
• [10] IRL 2500: A potent ETB selective endothelin antagonist, Bioorg. Med. Chem. Lett. 6(19):2323-2328 (1996).
• [11] Human optic nerve head astrocytes as a target for endothelin-1. Invest Ophthalmol Vis Sci. 2002 Aug;43(8):2704-13.
• [12] RES-701-1/endothelin-1 hybrid peptide having a potent binding activity for type B receptor, Bioorg. Med. Chem. Lett. 7(13):1715-1720 (1997).
• [13] Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity. J Med Chem. 1999 Sep 9;42(18):3668-78.
• [14] Res-701-1, synthesis and a reevaluation of its effects on the endothelin receptors, Bioorg. Med. Chem. Lett. 5(6):621-626 (1995).
• [15] Pharmacological differences between rat and human endothelin B receptors. Biochem Biophys Res Commun. 1995 Apr 17;209(2):506-12.
• [16] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 220).
• [17] cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8.
• [18] Influence of endothelin receptor antagonists on myocardial protein kinase C isoforms in uraemic cardiomyopathy. Clin Sci (Lond). 2002 Aug;103 Suppl 48:276S-279S.
• [19] gamma-Carbamate butenolide analogues as potent ETA selective endothelin receptor antagonists and prodrugs, Bioorg. Med. Chem. Lett. 7(3):297-302 (1997).
• [20] Analogs of an endothelin antagonist RES-701-1: substitutions of C-terminal amino acid, Bioorg. Med. Chem. Lett. 6(7):775-778 (1996).
• [21] Structure-activity relationships in a series of monocyclic endothelin analogues, Bioorg. Med. Chem. Lett. 4(4):567-572 (1994).