Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGY8IW)

• DTT Name: B2 bradykinin receptor (BDKRB2)
• Synonyms: Bradykinin B2 receptor; BKR2; BK-2 receptor; BK B(2) receptor; B2R
• Gene Name: BDKRB2
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: BKRB2_HUMAN
• TTD ID: T23714
• Sequence:
  MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQ
  PPFLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFWAITISNN
  FDWLFGETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLV
  IWGCTLLLSSPMLVFRTMKEYSDEGHNVTACVISYPSLIWEVFTNMLLNVVGFLLPLSVI
  TFCTMQIMQVLRNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGI
  LSSCQDERIIDVITQIASFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEP
  IQMENSMGTLRTSISVERQIHKLQDWAGSRQ
• Function: It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. Receptor for bradykinin.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  Sphingolipid signaling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Icatibant	DMQPTOZ	Hereditary angioedema	4A00.14	Approved	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Anatibant	DMG7IEN	Traumatic brain injury	NA07.Z	Phase 2	[2]
DELTIBANT	DM5CB8U	Sepsis	1G40-1G41	Phase 2	[3]
DM199	DM0157T	Cerebral ischemia	8B11	Phase 2	[4]
Fasitibant chloride	DM563NC	Osteoarthritis	FA00-FA05	Phase 2	[5]
BRADYKININ	DM4R6UV	N. A.	N. A.	Phase 1	[6]

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Labradimil	DMSFL76	Brain cancer	2A00	Discontinued in Phase 2	[7]
NPC-567	DMAVZ1F	Rhinitis	FA20	Discontinued in Phase 2	[8]
CP-0597	DMS23JX	Asthma	CA23	Terminated	[9]
FR-172357	DMY1LRI	Inflammation	1A00-CA43.1	Terminated	[10]
FR-173657	DM37OS4	N. A.	N. A.	Terminated	[11]
JSM-10292	DMU5TGC	Pain	MG30-MG3Z	Terminated	[12]
NPC-17731	DMGVIZY	Asthma	CA23	Terminated	[13]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(D)Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(d)Phe-Phe-Arg	DMWE42T	Discovery agent	N.A.	Investigative	[14]
(D)Arg-Arg-Pro-Hyp-Gly-Thi-Cys-(D)Phe-Phe-Cys-Arg	DMYSE3O	Discovery agent	N.A.	Investigative	[14]
(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Aoc-Arg	DMLSJKM	Discovery agent	N.A.	Investigative	[14]
(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Tic-Arg	DMP0627	Discovery agent	N.A.	Investigative	[14]
bradyzide	DM0DWSR	Discovery agent	N.A.	Investigative	[15]
Breceptin	DM21ZBU	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
chroman 28	DMVDB7S	Discovery agent	N.A.	Investigative	[17]
FR167344	DM2W5VA	Discovery agent	N.A.	Investigative	[18]
FR190997	DM0G4HP	Discovery agent	N.A.	Investigative	[19]
FR191413	DM75VHN	Discovery agent	N.A.	Investigative	[20]
H-DArg-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH(JMV1638)	DM6839G	Discovery agent	N.A.	Investigative	[6]
H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH(JMV1645)	DMDXIS7	Discovery agent	N.A.	Investigative	[6]
H-Lys-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-OH(JMV1669)	DMTGU0L	Discovery agent	N.A.	Investigative	[6]
JMV1431	DMAR3M2	Discovery agent	N.A.	Investigative	[6]
kallidin	DMRT6OP	Discovery agent	N.A.	Investigative	[21]
LF-160335	DMOEQTN	Discovery agent	N.A.	Investigative	[22]
Met-Lys-bradykinin	DMZBLQD	Discovery agent	N.A.	Investigative	[23]
NPC-349	DMU426Z	Discovery agent	N.A.	Investigative	[21]
PMID12723943C12	DMR1MCD	Discovery agent	N.A.	Investigative	[24]
PMID12812482C11	DMYXDK5	Discovery agent	N.A.	Investigative	[25]
PS020990	DMK6HMS	Discovery agent	N.A.	Investigative	[26]
Quinapril analogue	DM0BEZS	Discovery agent	N.A.	Investigative	[27]
T-kinin	DMYGXHK	Discovery agent	N.A.	Investigative	[28]
WIN 64338	DMTE0YJ	Discovery agent	N.A.	Investigative	[29]
[des-Arg9]bradykinin	DMEL0SZ	Discovery agent	N.A.	Investigative	[30]
[Leu8,des-Arg9]bradykinin	DM3JHRC	Discovery agent	N.A.	Investigative	[31]
[Sar,D-Phe8,des-Arg9]bradykinin	DMUF7DP	Discovery agent	N.A.	Investigative	[28]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoarthritis	FA20	Synovial tissue	8.79E-01	0.18	0.14
Sepsis with septic shock	1G41	Whole blood	8.95E-05	-0.13	-0.45
Neuroectodermal tumour	2C82	Nervous tissue	6.64E-04	-0.24	-0.54
Asthma	CA23	Nasal and bronchial airway	1.49E-01	0.11	0.2

References

• [1] Bradykinin receptor antagonists--a review of the patent literature 2005-2008. Expert Opin Ther Pat. 2009 Jul;19(7):919-41.
• [2] Inhibition of bradykinin B2 receptors before, not after onset of experimental subarachnoid hemorrhage prevents brain edema formation and improves functional outcome. Crit Care Med. 2009 Jul;37(7):2228-34.
• [3] CP-0127, a novel potent bradykinin antagonist, increases survival in rat and rabbit models of endotoxin shock. Agents Actions Suppl. 1992;38 ( Pt 3):413-20.
• [4] Pharmacological effects of recombinant human tissue kallikrein on bradykinin B2 receptors. Pharmacol Res Perspect. 2015 Mar;3(2):e00119.
• [5] Fasitibant chloride, a kinin B receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats. Br J Pharmacol. 2012 Jun;166(4):1403-10.
• [6] Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. J Med Chem. 2000 Jun 15;43(12):2382-6.
• [7] Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life. J Transl Med. 2009 May 13;7:33.
• [8] 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.
• [9] CP-0597, a selective bradykinin B2 receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion. Stroke. 1997 Jul;28(7):1430-6.
• [10] Characterization of FR 172357, a new non-peptide bradykinin B(2) receptor antagonist, in human, pig and rabbit preparations. Eur J Pharmacol. 1999 Dec 10;386(1):25-31.
• [11] Novel small molecule bradykinin B2 receptor antagonists. J Med Chem. 2009 Jul 23;52(14):4370-9.
• [12] Binding characteristics of [3H]-JSM10292: a new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist. Br J Pharmacol. 2012 Oct;167(4):839-53.
• [13] Antinociceptive profile of the pseudopeptide B2 bradykinin receptor antagonist NPC 18688 in mice. Br J Pharmacol. 1996 Feb;117(3):552-558.
• [14] Design and conformational analysis of several highly potent bradykinin receptor antagonists. J Med Chem. 1991 Mar;34(3):1230-3.
• [15] Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia. Br J Pharmacol. 2000 Jan;129(1):77-86.
• [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: 42).
• [17] Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity. J Med Chem. 2007 Feb 22;50(4):607-10.
• [18] Novel subtype-selective nonpeptide bradykinin receptor antagonists FR167344 and FR173657. Mol Pharmacol. 1997 Feb;51(2):171-6.
• [19] Nonpeptide mimic of bradykinin with long-acting properties at the bradykinin B2 receptor. Mol Pharmacol. 1997 Jul;52(1):16-20.
• [20] Discovery of the first non-peptide full agonists for the human bradykinin B(2) receptor incorporating 4-(2-picolyloxy)quinoline and 1-(2-picolyl)benzimidazole frameworks. J Med Chem. 2004 May 20;47(11):2853-63.
• [21] Differential pharmacology of cloned human and mouse B2 bradykinin receptors. Mol Pharmacol. 1994 Jan;45(1):1-8.
• [22] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [23] Expression cloning of a human B1 bradykinin receptor. J Biol Chem. 1994 Aug 26;269(34):21583-6.
• [24] Benzodiazepines as potent and selective bradykinin B1 antagonists. J Med Chem. 2003 May 8;46(10):1803-6.
• [25] Discovery of a potent, non-peptide bradykinin B1 receptor antagonist. J Am Chem Soc. 2003 Jun 25;125(25):7516-7.
• [26] Small molecule antagonists of the bradykinin B1 receptor. Immunopharmacology. 1999 Sep;43(2-3):169-77.
• [27] Ace inhibitors as a template for the design of bradykinin B2 receptor antagonists, Bioorg. Med. Chem. Lett. 5(4):367-370 (1995).
• [28] Molecular characterisation of cloned bradykinin B1 receptors from rat and human. Eur J Pharmacol. 1999 Jun 25;374(3):423-33.
• [29] Design of potent non-peptide competitive antagonists of the human bradykinin B2 receptor. J Med Chem. 1993 Aug 20;36(17):2583-4.
• [30] Stable expression of human kinin B1 receptor in 293 cells: pharmacological and functional characterization. Br J Pharmacol. 1997 Sep;122(2):393-9.
• [31] Partial agonists and full antagonists at the human and murine bradykinin B1 receptors. Can J Physiol Pharmacol. 1997 Jun;75(6):735-40.