Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5TKPM)

• DTT Name: Neutral endopeptidase (MME)
• Synonyms: Skin fibroblast elastase; SFE; Neutral endopeptidase 24.11; Neprilysin; NEP protein; Enkephalinase; EPN; Common acute lymphocytic leukemia antigen; CD10; CALLA; Atriopeptidase
• Gene Name: MME
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: NEP_HUMAN
• TTD ID: T05409
• EC Number: EC 3.4.24.11
• Sequence:
  MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
  DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD
  VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA
  SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE
  ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY
  NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT
  KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME
  NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI
  GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA
  VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
  GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR
  AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII
  GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW
• Function: Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers. Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Hematopoietic cell lineage (hsa04640)
  Protein digestion and absorption (hsa04974)
  Alzheimer's disease (hsa05010)
• Reactome Pathway: Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LCZ696	DMLFX7K	Heart failure	BD10-BD13	Approved	[1]

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Candoxatril	DMHJCGV	Hypertension	BA00-BA04	Phase 3	[2]
Gallopamil	DMXBR27	Asthma	CA23	Phase 2	[3]
Sampatrilat	DMXTOVE	Hypotension	BA20-BA21	Phase 2	[4]
SLV 306	DMCDON3	Acute decompensated heart failure	BD1Z	Phase 2	[5]
SLV-334	DMXCJKY	Brain injury	NA07.Z	Phase 2	[6]
VX-15	DMLWM4G	Huntington disease	8A01.10	Phase 2	[7]
CART-10 cells	DMQ4UJ6	Acute lymphoblastic leukaemia	2A85	Phase 1	[8]
CD10-CART	DM0XDYT	leukaemia	2A60-2B33	Phase 1	[9]
Debio 0827	DMQIEFB	Chronic pain	MG30	Phase 1	[10]
GW-796406	DMQ46DN	Hypotension	BA20-BA21	Phase 1	[3]
Pfizer 4	DMME5P8	Female sexual arousal dysfunction	HA01.1	Phase 1	[11]
SLV-338	DM7WKTM	Cardiovascular disease	BA00-BE2Z	Phase 1	[12]
TD-0714	DMO8L6T	Heart failure	BD10-BD13	Phase 1	[13]

18 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ilepatril	DMTR50E	Diabetic nephropathy	GB61.Z	Discontinued in Phase 2/3	[14]
CGS-25462	DM2OWCV	Hypertension	BA00-BA04	Discontinued in Phase 2	[15]
Fasidotril	DMRU1KT	Hypotension	BA20-BA21	Discontinued in Phase 2	[16]
Gemopatrilat	DMLMT5O	Hypotension	BA20-BA21	Discontinued in Phase 2	[17]
M-100240	DMQ1LWU	Hypotension	BA20-BA21	Discontinued in Phase 2	[18]
SCH-32615	DMAGBM2	Pain	MG30-MG3Z	Discontinued in Phase 2	[19]
Sch-34826	DMZR6GI	Hypertension	BA00-BA04	Discontinued in Phase 2	[20]
SCH-42495	DM2RH51	Hypotension	BA20-BA21	Discontinued in Phase 2	[21]
Candoxatrilat	DMQIWZL	Heart failure	BD10-BD13	Discontinued in Phase 1	[22]
BMS-182657	DM0K4DZ	Cardiovascular disease	BA00-BE2Z	Terminated	[23]
CGS-26303	DMFZM09	N. A.	N. A.	Terminated	[24]
CGS-26393	DM4U72A	Heart disease	BA41-BA42	Terminated	[25]
CGS-30440	DM94WIO	Hypertension	BA00-BA04	Terminated	[26]
GW-660511	DMG5A1Z	Hypertension	BA00-BA04	Terminated	[27]
Omapatrilat	DMAGUY0	Hypertension	BA00-BA04	Terminated	[28]
SCH-54470	DMEWLZ7	N. A.	N. A.	Terminated	[29]
SQ-26332	DM6SW2R	N. A.	N. A.	Terminated	[30]
SQ-28603	DM9DJFS	Hypertension	BA00-BA04	Terminated	[31]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
9-Mercaptomethyl-10-oxo-azecane-2-carboxylic acid	DMM2GQC	Discovery agent	N.A.	Investigative	[32]
CGS-314447	DM514L0	Discovery agent	N.A.	Investigative	[24]
fasidotrilat	DMC8G7X	Discovery agent	N.A.	Investigative	[33]
LBQ657	DMQ2DFN	Discovery agent	N.A.	Investigative	[34]
Phosphoramidon	DM3VL7G	Discovery agent	N.A.	Investigative	[35]
PMID18078750C1b	DMO21H5	Discovery agent	N.A.	Investigative	[36]
RB-105	DMRK3HO	Hypertension	BA00-BA04	Investigative	[37]
Thiorphan	DM86LFB	Discovery agent	N.A.	Investigative	[38]
[2(R,S)-2-Sulfanylheptanoyl]-Phe-Ala	DMI9RLZ	Discovery agent	N.A.	Investigative	[39]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Neprilysin (MME) DME Info
• Gene Name: MME

2 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Liraglutide	DM3FXPS	Non-insulin dependent diabetes	5A11	Approved	[40]
Semaglutide	DMAGFOD	Type-2 diabetes	5A11	Approved	[41]

References

• [1] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Clinical trials in traumatic brain injury: past experience and current developments.Neurotherapeutics.2010 Jan;7(1):115-26.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] ClinicalTrials.gov (NCT03291444) CAR-T Cells Combined With Peptide Specific Dendritic Cell in Relapsed/Refractory Leukemia/MDS
• [9] ClinicalTrials.gov (NCT03407859) Sequential Treatment With CD20/CD22/CD10-CART After CD19-CART Treatment Base on MRD in Relapsed/Refractory B-ALL
• [10] Clinical pipeline report, company report or official report of Debiopharm (2011).
• [11] Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66.
• [12] 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.
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension. Curr Opin Investig Drugs. 2008 Mar;9(3):301-9.
• [15] Quantitative analytical methods for the determination of a new hypertension drug, CGS 25462, and its metabolites (CGS 25659 and CGS 24592) in human plasma by high-performance liquid chromatography. JChromatogr B Biomed Sci Appl. 1998 Mar 20;706(2):287-94.
• [16] Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans. Hypertension. 2000 May;35(5):1148-53.
• [17] Omapatrilat.Bristol-Myers Squibb.Curr Opin Investig Drugs.2001 Oct;2(10):1414-22.
• [18] Effects of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase on the vasopressor response to exogenous angiot... J Cardiovasc Pharmacol. 1998 Mar;31(3):408-17.
• [19] The antinociceptive effects of SCH-32615, a neutral endopeptidase (enkephalinase) inhibitor, microinjected into the periaqueductal, ventral medulla and amygdala. Brain Res. 1990 Jun 18;520(1-2):123-30.
• [20] Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. J Pharmacol Exp Ther. 1988 Jun;245(3):829-38.
• [21] Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension. Hypertension. 1993 Jul;22(1):119-26.
• [22] 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.
• [23] Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure. J Pharmacol Exp Ther. 1995 Nov;275(2):745-52.
• [24] Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11, Bioorg. Med. Chem. Lett. 7(8):1059-1064 (1997).
• [25] Oral administration of an inhibitor of endothelin-converting enzyme attenuates cerebral vasospasm following experimental subarachnoid haemorrhage in rabbits. Clin Sci (Lond). 2002 Aug;103 Suppl 48:414S-417S.
• [26] Antihypertensive and natriuretic effects of CGS 30440, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase 24.11. J Pharmacol Exp Ther. 1998 Mar;284(3):974-82.
• [27] The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin. Br J Pharmacol. 2000 Feb;129(4):671-80.
• [28] Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice. Atherosclerosis. 2001 Apr;155(2):291-5.
• [29] Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors. J Med Chem. 2010 Jan 14;53(1):208-20.
• [30] Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
• [31] Evaluation of SQ 28,603, an inhibitor of neutral endopeptidase, in conscious monkeys. Can J Physiol Pharmacol. 1991 Oct;69(10):1609-17.
• [32] Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor. J Med Chem. 1993 Nov 26;36(24):3821-8.
• [33] Modelling of aldose reductase inhibitory activity of pyrrol-1-yl-acetic acid derivatives by means of multivariate statistics. Med Chem. 2005 Jul;1(4):321-6.
• [34] 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: 1611).
• [35] Neprilysin, a novel target for ultraviolet B regulation of melanogenesis via melanocortins. J Invest Dermatol. 2000 Sep;115(3):381-7.
• [36] Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite. Bioorg Med Chem Lett. 2008 Jan 15;18(2):732-7.
• [37] Reversal of cardiac hypertrophy and fibrosis by S21402, a dual inhibitor of neutral endopeptidase and angiotensin converting enzyme in SHRs. J Hypertens. 2000 Jun;18(6):749-55.
• [38] Thiorphan enhances bradykinin-induced vascular relaxation in hypoxic/hyperkalaemic porcine coronary artery. J Pharm Pharmacol. 2003 Mar;55(3):339-45.
• [39] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [40] Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53.
• [41] Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Eur J Pharm Sci. 2017 Jun 15;104:31-41.