Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT8DBY3)

• DTT Name: Angiotensin II receptor type-1 (AGTR1)
• Synonyms: Type-1 angiotensin II receptor; Angiotensin II type-1 receptor; Angiotensin II receptor 1; Angiotensin 1 receptor; AT2R1B; AT2R1; AT1BR; AT1AR; AT1; AGTR1B; AGTR1A
• Gene Name: AGTR1
• DTT Type: Successful target; [1]
• Related Disease:
  Essential hypertension [ICD-11: BA00]
  Hypertension [ICD-11: BA00-BA04]
  Secondary hypertension [ICD-11: BA04]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: AGTR1_HUMAN
• TTD ID: T74456
• Sequence:
  MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMKLK
  TVASVFLLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFLLT
  CLSIDRYLAIVHPMKSRLRRTMLVAKVTCIIIWLLAGLASLPAIIHRNVFFIENTNITVC
  AFHYESQNSTLPIGLGLTKNILGFLFPFLIILTSYTLIWKALKKAYEIQKNKPRNDDIFK
  IIMAIVLFFFFSWIPHQIFTFLDVLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPL
  FYGFLGKKFKRYFLQLLKYIPPKAKSHSNLSTKMSTLSYRPSDNVSSSTKKPAPCFEVE
• Function: Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Receptor for angiotensin II.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Renin-angiotensin system (hsa04614)
  Renin secretion (hsa04924)
  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

15 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Angiotensin Ii	DMLWQ27	Increase blood pressure	BA04	Approved	[2]
Azilsartan	DMOIX5S	Hypertension	BA00-BA04	Approved	[3]
Candesartan	DMRK8OT	Hypertension	BA00-BA04	Approved	[4], [5], [6]
Eprosartan	DM07K2I	Hypertension	BA00-BA04	Approved	[7], [8]
Forasartan	DMRBJNZ	Hypertension	BA00-BA04	Approved	[9], [10]
Irbesartan	DMTP1DC	Hypertension	BA00-BA04	Approved	[1], [11]
Losartan	DM72JXH	Hypertension	BA00-BA04	Approved	[1], [12], [13], [14]
Micardis telmisartan	DM3O6CY	Hypertension	BA00-BA04	Approved	[15]
Olmesartan medoxomil	DMWBHRY	High blood pressure	BA00	Approved	[16]
Saprisartan	DM4087K	Hypertension	BA00-BA04	Approved	[17]
SARALASIN	DMKS1DV	Hypertension	BA00-BA04	Approved	[18]
Saralasin Acetate	DMKZROL	Hypertension	BA00-BA04	Approved	[19]
Tasosartan	DMM13DI	Hypertension	BA00-BA04	Approved	[20]
Telmisartan	DMS3GX2	Hypertension	BA00-BA04	Approved	[21]
Valsartan	DMREUQ6	Hypertension	BA00-BA04	Approved	[1], [12], [22]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pratosartan	DMOMDXI	Hypertension	BA00-BA04	Phase 3	[23]
S-474474	DM408GM	Metabolic syndrome x	5C50-5D2Z	Phase 3	[24]
sparsentan	DMMP51W	Focal segmental glomerulosclerosis	MF8Y	Phase 3	[25]
TAK-491	DMCF6SX	Hypertension	BA00-BA04	Phase 3	[3]
CL-329167	DMSF7WJ	Hypertension	BA00-BA04	Phase 2	[26], [27]
TRV027	DMVX6H0	Heart failure	BD10-BD13	Phase 2	[28]
YM-358	DMS7609	Hypertension	BA00-BA04	Phase 2	[29], [27]

14 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KRH-594	DMIJ6FX	Hypertension	BA00-BA04	Discontinued in Phase 2	[30]
MILFASARTAN	DMTX97J	Hypertension	BA00-BA04	Discontinued in Phase 2	[31], [27]
RIPISARTAN	DME5MGP	Hypertension	BA00-BA04	Discontinued in Phase 2	[32], [27]
Zolasartan	DM9FQI0	Hypotension	BA20-BA21	Discontinued in Phase 2	[33]
TAK-591	DM25DB4	Hypertension	BA00-BA04	Discontinued in Phase 1	[34]
UR-7198	DMXN9Z5	Hypertension	BA00-BA04	Discontinued in Phase 1	[35]
A-81988	DM1GLIN	Hypertension	BA00-BA04	Terminated	[36]
CR-3834	DMTPDX7	Hypertension	BA00-BA04	Terminated	[37]
HELENALIN	DMMCI4H	N. A.	N. A.	Terminated	[38]
L-158809	DMQ4LDB	Hypertension	BA00-BA04	Terminated	[39]
L-159689	DM9JE7Y	Hypertension	BA00-BA04	Terminated	[25]
RS-66252	DMT5DH0	Alzheimer disease	8A20	Terminated	[40]
UP-275-22	DM37DOC	Hypertension	BA00-BA04	Terminated	[41]
XR-510	DMA13OD	Hypertension	BA00-BA04	Terminated	[42]

31 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n	DMW3RJL	Discovery agent	N.A.	Investigative	[43]
4-(2-Butyl-benzoimidazol-1-ylmethyl)-phenol	DM8HLEP	Discovery agent	N.A.	Investigative	[44]
4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone	DMTZ9G3	Discovery agent	N.A.	Investigative	[45]
4-[(diphenylmethyl)amino]-2-phenylquinazoline	DMT1PM4	Discovery agent	N.A.	Investigative	[46]
5-butyl-methyl immidazole carboxylate 30	DM0VGCX	Discovery agent	N.A.	Investigative	[47]
5-oxo-1-2-4-oxadiazol biphenyl	DME62OQ	Discovery agent	N.A.	Investigative	[48]
angiotensin III	DMYK0Z9	Discovery agent	N.A.	Investigative	[41]
CGP-49870	DM5SATN	Discovery agent	N.A.	Investigative	[49]
CV-11194	DMEB0FX	Discovery agent	N.A.	Investigative	[50]
EXP3174	DMWIBFM	Discovery agent	N.A.	Investigative	[51], [52]
GNF-PF-2307	DMP6DBX	Discovery agent	N.A.	Investigative	[38]
GNF-PF-2812	DMD1QOH	Discovery agent	N.A.	Investigative	[38]
GNF-PF-3832	DMIY79U	Discovery agent	N.A.	Investigative	[38]
INC-106	DM8E4HB	Artery stenosis	BD52	Investigative	[41]
L-159093	DMOX8JE	Discovery agent	N.A.	Investigative	[25]
L-162313	DMZOW96	Discovery agent	N.A.	Investigative	[53]
L-162782	DMWSP6H	Discovery agent	N.A.	Investigative	[53]
L-163,101	DMYC7AK	Discovery agent	N.A.	Investigative	[54]
LY301875	DM2HQ9O	Discovery agent	N.A.	Investigative	[55]
LY303336	DMY9WTE	Discovery agent	N.A.	Investigative	[55]
N,N`-bis-alkyl butylimmidazole 12b	DMNZKCL	Discovery agent	N.A.	Investigative	[56]
[125I]EXP985	DMEKGZS	Discovery agent	N.A.	Investigative	[57]
[3H]GBR12935	DMGQDLU	Discovery agent	N.A.	Investigative	[58]
[Bpa1]AngII	DMB78GP	Discovery agent	N.A.	Investigative	[2]
[Sar1,Bpa2]AngII	DM1HQ3D	Discovery agent	N.A.	Investigative	[2]
[Sar1,Bpa3]AngII	DMP64XH	Discovery agent	N.A.	Investigative	[2]
[Sar1,Bpa8]AngII	DMWC10R	Discovery agent	N.A.	Investigative	[2]
[Sar1,Tdf2]AngII	DM4AUFR	Discovery agent	N.A.	Investigative	[2]
[Sar1,Tdf3]AngII	DMWCS4Y	Discovery agent	N.A.	Investigative	[2]
[Sar1,Tdf8]AngII	DMTNGCW	Discovery agent	N.A.	Investigative	[2]
[Tdf1]AngII	DMN0BT3	Discovery agent	N.A.	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	8.95E-01	1.34E-02	0.07

References

• [1] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [2] The amino-terminus of angiotensin II contacts several ectodomains of the angiotensin II receptor AT1. J Med Chem. 2010 Mar 11;53(5):2063-75.
• [3] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [4] Candesartan: widening indications for this angiotensin II receptor blocker Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007.
• [5] Angiotensin II type 1 receptor blockade: a novel therapeutic concept. Blood Press Suppl. 2000;1:9-13.
• [6] Binding of the antagonist [3H]candesartan to angiotensin II AT1 receptor-transfected [correction of tranfected] Chinese hamster ovary cells. Eur J Pharmacol. 1999 Feb 19;367(2-3):413-22.
• [7] Clinical profile of eprosartan: a different angiotensin II receptor blocker. Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):253-7.
• [8] Characterization of [3H]SK&F 108566 as a radioligand for angiotensin type-1 receptor. J Recept Res. 1993;13(5):849-61.
• [9] Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification. J Med Chem. 2003 Feb 27;46(5):716-26.
• [10] Possible involvement of calcium-calmodulin pathways in the positive chronotropic response to angiotensin II on the canine cardiac sympathetic ganglia. Jpn J Pharmacol. 2001 Aug;86(4):381-9.
• [11] Binding characteristics of [(3)H]-irbesartan to human recombinant angiotensin type 1 receptors. J Renin Angiotensin Aldosterone Syst. 2000 Jun;1(2):159-65.
• [12] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [13] Effect of episodic hypoxia on sympathetic activity and blood pressure. Respir Physiol. 2000 Feb;119(2-3):189-97.
• [14] Characterization of [3H]losartan receptors in isolated rat glomeruli. Eur J Pharmacol. 1993 Oct 15;247(2):193-8.
• [15] The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial. J Hypertens. 2005 Nov;23(11):2055-61.
• [16] Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers. J Cardiovasc Pharmacol. 2009 Jul;54(1):47-56.
• [17] Pharmacological properties of angiotensin II receptor antagonists. Can J Cardiol. 1999 Nov;15 Suppl F:26F-8F.
• [18] Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. J Med Chem. 2008 Jul 24;51(14):4150-69.
• [19] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [20] Tasosartan, enoltasosartan, and angiotensin II receptor blockade: the confounding role of protein binding. J Pharmacol Exp Ther. 2000 Nov;295(2):649-54.
• [21] Deletion of angiotensin II type I receptor reduces hepatic steatosis. J Hepatol. 2009 Jun;50(6):1226-35.
• [22] Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors. Fundam Clin Pharmacol. 2000 Nov-Dec;14(6):577-85.
• [23] Clinical efficacy of a new angiotensin II type 1 receptor blocker, pratosartan, in hypertensive patients. Hypertens Res. 2008 Feb;31(2):281-7.
• [24] Clinical pipeline report, company report or official report of Shionogi (2011).
• [25] Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
• [26] Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts. Am J Physiol. 1994 Aug;267(2 Pt 2):H844-52.
• [27] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [28] First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol. 2013 Sep;53(9):892-9.
• [29] Effects of YM358, an angiotensin II type 1 (AT1) receptor antagonist, and enalapril on blood pressure and vasoconstriction in two renal hypertension models. Biol Pharm Bull. 2000 Feb;23(2):174-81.
• [30] Binding of KRH-594, an antagonist of the angiotensin II type 1 receptor, to cloned human and rat angiotensin II receptors. Fundam Clin Pharmacol. 2002 Aug;16(4):317-23.
• [31] Dual action molecules: bioassays of combined novel antioxidants and angiotensin II receptor antagonists. Eur J Pharmacol. 2012 Nov 15;695(1-3):96-103.
• [32] In vitro pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist. Fundam Clin Pharmacol. 1995;9(2):119-28.
• [33] Azilsartan: a newly approved angiotensin II receptor blocker. Cardiol Rev. 2011 Nov-Dec;19(6):300-4.
• [34] Clinical pipeline report, company report or official report of Takeda (2009).
• [35] Pharmacologic profile of UR-7247, an orally active angiotensin II AT1 receptor antagonist, in healthy volunteers. p6. J Cardiovasc Pharmacol. 2000 Mar;35(3):383-9.
• [36] [3H]A-81988, a potent, selective, competitive antagonist radioligand for angiotensin AT1 receptors. Eur J Pharmacol. 1994 Mar 15;267(1):49-54.
• [37] Pharmacokinetic study of a new angiotensin-AT1 antagonist by HPLC. J Pharm Biomed Anal. 2008 Sep 29;48(2):422-7.
• [38] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [39] Characterization of the binding of [3H]L-158,809: a new potent and selective nonpeptide angiotensin II receptor (AT1) antagonist radioligand. Mol Pharmacol. 1992 Dec;42(6):1077-82.
• [40] Virtual Screening in Drug Discovery, Juan Alvarez Brian Shoichet. Page(218).
• [41] 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: 34).
• [42] Pharmacology of XR510, a potent orally active nonpeptide angiotensin II AT1 receptor antagonist with high affinity for the AT2 receptor subtype. J Cardiovasc Pharmacol. 1995 Sep;26(3):354-62.
• [43] Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther. 1999 Nov;291(2):648-54.
• [44] Discovery and development of aryl-fused imidazole-based angiotensin II antagonists, Bioorg. Med. Chem. Lett. 4(1):213-218 (1994).
• [45] Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies. J Med Chem. 2000 Feb 10;43(3):351-60.
• [46] Identification of a novel partial inhibitor of dopamine transporter among 4-substituted 2-phenylquinazolines. Bioorg Med Chem Lett. 2002 Aug 19;12(16):2225-8.
• [47] The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: a concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives. Eur J Med Chem. 2012 Sep;55:358-74.
• [48] Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect. Bioorg Med Chem. 2012 Apr 15;20(8):2747-61.
• [49] Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and AT1 receptor antagonists
• [50] Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisoste... J Med Chem. 1996 Dec 20;39(26):5228-35.
• [51] Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993 Jun;45(2):205-51.
• [52] Angiotensin II receptor antagonists: imidazoles and pyrroles bearing hydroxymethyl and carboxy substituents, Bioorg. Med. Chem. Lett. 4(1):177-182 (1994).
• [53] Selective angiotensin II AT2 receptor agonists: Benzamide structure-activity relationships. Bioorg Med Chem. 2008 Jul 15;16(14):6841-9.
• [54] Structural model of antagonist and agonist binding to the angiotensin II, AT1 subtype, G protein coupled receptor. Chem Biol. 1994 Dec;1(4):211-21.
• [55] Inhibition of angiotensin II-induced inositol phosphate production by triacid nonpeptide antagonists in CHO cells expressing human AT1 receptors. Pharm Res. 2000 Dec;17(12):1482-8.
• [56] Rational design, efficient syntheses and biological evaluation of N,N'-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers. Eur J Med Chem. 2013 Apr;62:352-70.
• [57] [125I]EXP985: a highly potent and specific nonpeptide radioligand antagonist for the AT1 angiotensin receptor. Biochem Biophys Res Commun. 1992 Nov 16;188(3):1030-9.
• [58] Specific binding of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl propyl) piperazine (GBR-12935), an inhibitor of the dopamine transporter, to human CYP2D6. Biochem Pharmacol. 1997 Jun 15;53(12):1937-9.