Details of the Drug Combination

General Information of Drug Combination (ID: DCJMZRD)

• Drug Combination Name: Benazepril + Candesartan
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Benazepril (DMH1M9B): Small molecular drug
  Candesartan (DMRK8OT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Benazepril

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]
Malignant essential hypertension	BA00	Approved	[3]

Benazepril Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[6]

Benazepril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[7]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[7]

Benazepril Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Methylenetetrahydrofolate reductase (MTHFR)	DEOXTPZ	MTHR_HUMAN	Metabolism	[8]

Benazepril Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Methylenetetrahydrofolate reductase (MTHFR)	OTUBJSR7	MTHR_HUMAN	Affects Response To Substance	[9]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Decreases Expression	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[11]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[12]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[12]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[10]
Protein AMBP (AMBP)	OTLU8GU8	AMBP_HUMAN	Decreases Expression	[13]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[10]
Methionine synthase (MTR)	OTF2K2TA	METH_HUMAN	Affects Response To Substance	[8]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Affects Response To Substance	[14]
Lysosomal Pro-X carboxypeptidase (PRCP)	OTIUY91L	PCP_HUMAN	Affects Response To Substance	[15]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Response To Substance	[17]

Indication(s) of Candesartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[4]

Candesartan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[19]

Candesartan Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[22]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[23]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[22]

Candesartan Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[24]
Carbonic anhydrase 1 (CA1)	OTNFBVVQ	CAH1_HUMAN	Decreases Activity	[25]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[26]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[18]
Cytochrome b-245 light chain (CYBA)	OT16N9ZO	CY24A_HUMAN	Decreases Expression	[27]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Increases Expression	[28]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[29]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[30]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[29]
NADPH oxidase 4 (NOX4)	OTTYQ097	NOX4_HUMAN	Decreases Expression	[27]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Affects Response To Substance	[31]

References

• [1] ClinicalTrials.gov (NCT04467931) ACEI or ARB and COVID-19 Severity and Mortality in US Veterans
• [2] 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. (Ligand id: 6374).
• [3] Amlodipine FDA Label
• [4] Candesartan FDA Label
• [5] 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. (Ligand id: 587).
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• [7] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [8] Effects of MTHFR and MS gene polymorphisms on baseline blood pressure and Benazepril effectiveness in Chinese hypertensive patients. J Hum Hypertens. 2011 Mar;25(3):172-7.
• [9] A common haplotype on methylenetetrahydrofolate reductase gene modifies the effect of angiotensin-converting enzyme inhibitor on blood pressure in essential hypertension patients--a family-based association study. Clin Exp Hypertens. 2005 Aug;27(6):509-21.
• [10] Expression of toll-like receptor 4, tumor necrosis factor- alpha, matrix metalloproteinase-9 and effects of benazepril in patients with acute coronary syndromes. Clin Med Insights Cardiol. 2010 Oct 11;4:89-93. doi: 10.4137/CMC.S5659.
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• [12] Transforming growth factor-beta1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker. Nephrol Dial Transplant. 2008 Sep;23(9):2841-6. doi: 10.1093/ndt/gfn159. Epub 2008 Apr 5.
• [13] Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scand J Urol Nephrol. 2005;39(6):511-7. doi: 10.1080/00365590510031264.
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• [15] E112D polymorphism in the prolylcarboxypeptidase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Chin Med J (Engl). 2009 Oct 20;122(20):2461-5.
• [16] Beta2 adrenergic receptor gene Arg16Gly polymorphism is associated with therapeutic efficacy of benazepril on essential hypertension in Chinese. Clin Exp Hypertens. 2004 Aug;26(6):581-92. doi: 10.1081/ceh-200031839.
• [17] Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J Hum Hypertens. 2016 Dec;30(12):766-771. doi: 10.1038/jhh.2016.24. Epub 2016 Apr 28.
• [18] Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer. Clin Cancer Res. 2006 May 1;12(9):2888-93. doi: 10.1158/1078-0432.CCR-05-2213.
• [19] Candesartan: widening indications for this angiotensin II receptor blocker Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007.
• [20] The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol. 2008 Sep 15;76(6):763-72.
• [21] Product Monograph of Atacand.
• [22] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [23] Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013 Nov;41(11):1888-95.
• [24] A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes. Cardiovasc Drugs Ther. 2008 Dec;22(6):469-78. doi: 10.1007/s10557-008-6131-x. Epub 2008 Aug 5.
• [25] The mechanism of action of angiotensin II is dependent on direct activation of vascular smooth muscle carbonic anhydrase I. Int J Clin Lab Res. 2000;30(3):119-25. doi: 10.1007/s005990070010.
• [26] Candesartan reduces oxidative stress and inflammation in patients with essential hypertension. Hypertens Res. 2003 Sep;26(9):691-7. doi: 10.1291/hypres.26.691.
• [27] Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008 Jul;26(7):1435-45. doi: 10.1097/HJH.0b013e3283013b6e.
• [28] Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor- activation in human monocytes. J Hypertens. 2012 Jan;30(1):87-96. doi: 10.1097/HJH.0b013e32834dde5f.
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• [30] Distinct vascular and metabolic effects of different classes of anti-hypertensive drugs. Int J Cardiol. 2010 Apr 1;140(1):73-81. doi: 10.1016/j.ijcard.2008.11.017. Epub 2008 Dec 6.
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