Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMQIWZL)

• Drug Name: Candoxatrilat Drug Info
• Synonyms: Candoxatrilat < Rec INN; UK-69578; UK-73967; Cis-4-[[[1-[2-Carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonyl]amino]cyclohexanecarboxylic acid; (+)-cis-4-[1-[(S)-2-Carboxy-3-(2-methoxyethoxy)propyl]cyclopentylcarbonylamino]cyclohexanecarboxylic acid; 3-[1-(4-cis-Carboxycyclohexylcarbamoyl)cyclopentyl]-2(R,S)-(2-methoxyethoxymethyl)propanoic acid

Indication

Disease Entry	ICD 11	Status	REF
Heart failure	BD10-BD13	Discontinued in Phase 1	[1]

• Cross-matching ID:
  PubChem CID: 443380
  ChEBI ID: CHEBI:3354
  CAS Number: CAS 123122-54-3
  TTD Drug ID: DMQIWZL

Molecule-Related Drug Atlas

Drug(s) Targeting Neutral endopeptidase (MME)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LCZ696	DMLFX7K	Heart failure	BD10-BD13	Approved	[4]
Candoxatril	DMHJCGV	Hypertension	BA00-BA04	Phase 3	[5]
Gallopamil	DMXBR27	Asthma	CA23	Phase 2	[6]
SLV 306	DMCDON3	Acute decompensated heart failure	BD1Z	Phase 2	[7]
SLV-334	DMXCJKY	Brain injury	NA07.Z	Phase 2	[8]
VX-15	DMLWM4G	Huntington disease	8A01.10	Phase 2	[9]
Sampatrilat	DMXTOVE	Hypotension	BA20-BA21	Phase 2	[10]
SLV-338	DM7WKTM	Cardiovascular disease	BA00-BE2Z	Phase 1	[11]
GW-796406	DMQ46DN	Hypotension	BA20-BA21	Phase 1	[6]
Debio 0827	DMQIEFB	Chronic pain	MG30	Phase 1	[12]

Drug(s) Affected By Neprilysin (MME)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ciclosporin	DMAZJFX	Graft-versus-host disease	4B24	Approved	[13]
Fulvestrant	DM0YZC6	Breast cancer	2C60-2C65	Approved	[14]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[15]
Marinol	DM70IK5	Anorexia nervosa cachexia	6B80	Approved	[16]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[17]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[18]
Niclosamide	DMJAGXQ	Cestodes infection	1F70-1F76	Approved	[19]
Temozolomide	DMKECZD	Adenocarcinoma	2D40	Approved	[20]
Arsenic	DMTL2Y1	N. A.	N. A.	Approved	[21]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[22]

Drug(s) Affected By Membrane metallo-endopeptidase-like 1 (MMEL1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[23]
Zoledronate	DMIXC7G	Adenocarcinoma	2D40	Approved	[24]
Arsenic	DMTL2Y1	N. A.	N. A.	Approved	[25]
Benzo(a)pyrene	DMN7J43	N. A.	N. A.	Phase 1	[26]
Omapatrilat	DMAGUY0	Hypertension	BA00-BA04	Terminated	[3]
bisphenol A	DM2ZLD7	Discovery agent	N.A.	Investigative	[27]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Neutral endopeptidase (MME)	TT5TKPM	NEP_HUMAN	Inhibitor	[2]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Membrane metallo-endopeptidase-like 1 (MMEL1)	OTOGJEXZ	MMEL1_HUMAN	Gene/Protein Processing	[3]
Neprilysin (MME)	OT5Q39P8	NEP_HUMAN	Gene/Protein Processing	[3]

References

• [1] 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: 6491).
• [2] Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension. J Hypertens. 1992 Mar;10(3):271-7.
• [3] Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol. 2008 Mar;153(5):947-55. doi: 10.1038/sj.bjp.0707641. Epub 2007 Dec 17.
• [4] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [5] Neutral endopeptidase inhibitor suppresses the early phase of atrial electrical remodeling in a canine rapid atrial pacing model. Indian Pacing Electrophysiol J. 2008 Apr 1;8(2):102-13.
• [6] Mechanism of vasopeptidase inhibitor-induced plasma extravasation: comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-converting enzyme inhibitor GW796406. J Pharmacol Exp Ther. 2005 Dec;315(3):1306-13.
• [7] The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans. Life Sci. 2012 Oct 15;91(13-14):743-8.
• [8] Clinical trials in traumatic brain injury: past experience and current developments.Neurotherapeutics.2010 Jan;7(1):115-26.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects. Am J Hypertens. 1999 Jun;12(6):563-71.
• [11] Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage. Clin Lab. 2011;57(7-8):507-15.
• [12] Clinical pipeline report, company report or official report of Debiopharm (2011).
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [19] Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist-mediated CD10 expression. Environ Toxicol. 2018 Jun;33(6):659-669.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.