Target General Infomation
Target ID
T05409 (Former ID: TTDS00449)
Target 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
Target Type
Clinical trial target
[1]
Disease [+] 1 Target-related Diseases +
1 Heart failure [ICD-11: BD10-BD1Z]
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.
BioChemical Class
Peptidase
UniProt ID
NEP_HUMAN
EC Number
EC 3.4.24.11
Sequence
MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD
VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA
SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE
ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY
NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT
KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME
NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI
GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA
VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR
AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII
GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW
Drugs and Modes of Action
Approved Drug(s) [+] 1 Approved Drugs +
1 LCZ696 Drug Info Approved Heart failure [1]
Clinical Trial Drug(s) [+] 13 Clinical Trial Drugs +
1 Candoxatril Drug Info Phase 3 Hypertension [2], [3]
2 Gallopamil Drug Info Phase 2 Asthma [4]
3 Sampatrilat Drug Info Phase 2 Hypotension [5]
4 SLV 306 Drug Info Phase 2 Acute decompensated heart failure [6], [7]
5 SLV-334 Drug Info Phase 2 Brain injury [8]
6 VX-15 Drug Info Phase 2 Huntington disease [9]
7 CART-10 cells Drug Info Phase 1 Acute lymphoblastic leukaemia [10]
8 CD10-CART Drug Info Phase 1 leukaemia [11]
9 Debio 0827 Drug Info Phase 1 Chronic pain [12]
10 GW-796406 Drug Info Phase 1 Hypotension [13]
11 Pfizer 4 Drug Info Phase 1 Female sexual arousal dysfunction [14]
12 SLV-338 Drug Info Phase 1 Cardiovascular disease [15]
13 TD-0714 Drug Info Phase 1 Heart failure [16]
Discontinued Drug(s) [+] 15 Discontinued Drugs +
1 Ilepatril Drug Info Discontinued in Phase 2/3 Diabetic nephropathy [17]
2 CGS-25462 Drug Info Discontinued in Phase 2 Hypertension [18]
3 Fasidotril Drug Info Discontinued in Phase 2 Hypotension [19], [20]
4 Gemopatrilat Drug Info Discontinued in Phase 2 Hypotension [21]
5 M-100240 Drug Info Discontinued in Phase 2 Hypotension [22]
6 SCH-32615 Drug Info Discontinued in Phase 2 Pain [23]
7 Sch-34826 Drug Info Discontinued in Phase 2 Hypertension [24]
8 SCH-42495 Drug Info Discontinued in Phase 2 Hypotension [25]
9 Candoxatrilat Drug Info Discontinued in Phase 1 Heart failure [26], [27]
10 BMS-182657 Drug Info Terminated Cardiovascular disease [28]
11 CGS-26393 Drug Info Terminated Heart disease [29]
12 CGS-30440 Drug Info Terminated Hypertension [30]
13 GW-660511 Drug Info Terminated Hypertension [31]
14 Omapatrilat Drug Info Terminated Hypertension [32]
15 SQ-28603 Drug Info Terminated Hypertension [33]
Mode of Action [+] 4 Modes of Action +
Modulator [+] 19 Modulator drugs +
1 LCZ696 Drug Info [1]
2 Sampatrilat Drug Info [5], [37]
3 SLV 306 Drug Info [8], [38]
4 SLV-334 Drug Info [39]
5 GW-796406 Drug Info [36]
6 SLV-338 Drug Info [15], [40]
7 Ilepatril Drug Info [17]
8 CGS-25462 Drug Info [42]
9 Fasidotril Drug Info [43]
10 Gemopatrilat Drug Info [44]
11 M-100240 Drug Info [45], [46]
12 Sch-34826 Drug Info [48]
13 BMS-182657 Drug Info [28]
14 CGS-26393 Drug Info [52]
15 CGS-30440 Drug Info [30]
16 GW-660511 Drug Info [31]
17 Omapatrilat Drug Info [32]
18 SQ-28603 Drug Info [55]
19 RB-105 Drug Info [61], [62], [63]
Inhibitor [+] 20 Inhibitor drugs +
1 Candoxatril Drug Info [34], [35]
2 Gallopamil Drug Info [36]
3 Debio 0827 Drug Info [12]
4 Pfizer 4 Drug Info [14]
5 TD-0714 Drug Info [16]
6 VX-15 Drug Info [41]
7 SCH-32615 Drug Info [8], [47]
8 SCH-42495 Drug Info [8], [49]
9 Candoxatrilat Drug Info [8], [50]
10 CGS-26303 Drug Info [51]
11 SCH-54470 Drug Info [53]
12 SQ-26332 Drug Info [54]
13 9-Mercaptomethyl-10-oxo-azecane-2-carboxylic acid Drug Info [56]
14 CGS-314447 Drug Info [51]
15 fasidotrilat Drug Info [57]
16 LBQ657 Drug Info [58]
17 Phosphoramidon Drug Info [59]
18 PMID18078750C1b Drug Info [60]
19 Thiorphan Drug Info [64]
20 [2(R,S)-2-Sulfanylheptanoyl]-Phe-Ala Drug Info [65]
CAR-T-Cell-Therapy [+] 1 CAR-T-Cell-Therapy drugs +
1 CART-10 cells Drug Info [10]
CAR-T-Cell-Therapy(Dual specific) [+] 1 CAR-T-Cell-Therapy(Dual specific) drugs +
1 CD10-CART Drug Info [11]
Target Regulators
Target-regulating Transcription Factors
Target Affiliated Biological Pathways
KEGG Pathway [+] 4 KEGG Pathways +
1 Renin-angiotensin system
2 Hematopoietic cell lineage
3 Protein digestion and absorption
4 Alzheimer's disease
NetPath Pathway [+] 2 NetPath Pathways +
1 EGFR1 Signaling Pathway
2 TGF_beta_Receptor Signaling Pathway
Reactome [+] 1 Reactome Pathways +
1 Metabolism of Angiotensinogen to Angiotensins
WikiPathways [+] 3 WikiPathways +
1 Metabolism of Angiotensinogen to Angiotensins
2 Primary Focal Segmental Glomerulosclerosis FSGS
3 Alzheimers Disease
Target-Related Models and Studies
Target Validation
References
REF 1 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
REF 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: 6492).
REF 3 Drug information of Candoxatril, 2008. eduDrugs.
REF 4 ClinicalTrials.gov (NCT00896428) Effects of Gallopamil in Severe Asthma (REMODEL'ASTHME) in University Hospital, Bordeaux.
REF 5 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.
REF 6 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: 6506).
REF 7 ClinicalTrials.gov (NCT00160225) Study to Evaluate the Efficacy and Safety of Daglutril Compared to Placebo on Top of Losartan in Type 2 Diabetics With Overt Nephropathy and Well Controlled Hypertension. U.S. National Institutes of Health.
REF 8 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.
REF 9 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 10 ClinicalTrials.gov (NCT03291444) CAR-T Cells Combined With Peptide Specific Dendritic Cell in Relapsed/Refractory Leukemia/MDS
REF 11 ClinicalTrials.gov (NCT03407859) Sequential Treatment With CD20/CD22/CD10-CART After CD19-CART Treatment Base on MRD in Relapsed/Refractory B-ALL
REF 12 Clinical pipeline report, company report or official report of Debiopharm (2011).
REF 13 Mechanism of vasopeptidase inhibitor-induced plasma extravasation: comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-... J Pharmacol Exp Ther. 2005 Dec;315(3):1306-13.
REF 14 Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66.
REF 15 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.
REF 16 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 17 Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension. Curr Opin Investig Drugs. 2008 Mar;9(3):301-9.
REF 18 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002979)
REF 19 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: 6501).
REF 20 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003997)
REF 21 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009581)
REF 22 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002832)
REF 23 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002402)
REF 24 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000196)
REF 25 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002070)
REF 26 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).
REF 27 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001740)
REF 28 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.
REF 29 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005940)
REF 30 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.
REF 31 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.
REF 32 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.
REF 33 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000347)
REF 34 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.
REF 35 Dual inhibition of angiotensin converting enzyme and neutral endopeptidase produces effective blood pressure control in spontaneously hypertensive rats. Bratisl Lek Listy. 2005;106(12):407-11.
REF 36 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.
REF 37 Sampatrilat Shire. Curr Opin Investig Drugs. 2002 Apr;3(4):578-81.
REF 38 Effect of single doses of SLV306, an inhibitor of both neutral endopeptidase and endothelin-converting enzyme, on pulmonary pressures in congestive heart failure. Am J Cardiol. 2004 Jul 15;94(2):237-9.
REF 39 Clinical trials in traumatic brain injury: past experience and current developments.Neurotherapeutics.2010 Jan;7(1):115-26.
REF 40 Endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 prevents hypertensive cardiac remodeling in a blood pressure-independent manner.Hypertension.2011 Apr;57(4):755-63.
REF 41 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 42 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.
REF 43 Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans. Hypertension. 2000 May;35(5):1148-53.
REF 44 Omapatrilat.Bristol-Myers Squibb.Curr Opin Investig Drugs.2001 Oct;2(10):1414-22.
REF 45 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.
REF 46 Comparative effects of the dual ACE-NEP inhibitor MDL-100,240 and ramipril on hypertension and cardiovascular disease in endogenous angiotensin II-... Am J Hypertens. 2002 Feb;15(2 Pt 1):181-8.
REF 47 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.
REF 48 Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. J Pharmacol Exp Ther. 1988 Jun;245(3):829-38.
REF 49 Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension. Hypertension. 1993 Jul;22(1):119-26.
REF 50 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.
REF 51 Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11, Bioorg. Med. Chem. Lett. 7(8):1059-1064 (1997).
REF 52 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.
REF 53 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.
REF 54 Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
REF 55 Evaluation of SQ 28,603, an inhibitor of neutral endopeptidase, in conscious monkeys. Can J Physiol Pharmacol. 1991 Oct;69(10):1609-17.
REF 56 Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor. J Med Chem. 1993 Nov 26;36(24):3821-8.
REF 57 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.
REF 58 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).
REF 59 Neprilysin, a novel target for ultraviolet B regulation of melanogenesis via melanocortins. J Invest Dermatol. 2000 Sep;115(3):381-7.
REF 60 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.
REF 61 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.
REF 62 Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase, in healthy subjects with hypovol... Clin Pharmacol Ther. 2002 Jun;71(6):468-78.
REF 63 Beneficial renal and cardiac effects of vasopeptidase inhibition with S21402 in heart failure. Hypertension. 2000 Dec;36(6):1105-11.
REF 64 Thiorphan enhances bradykinin-induced vascular relaxation in hypoxic/hyperkalaemic porcine coronary artery. J Pharm Pharmacol. 2003 Mar;55(3):339-45.
REF 65 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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