Target Information
Target General Infomation | |||||
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Target ID |
T05409
(Former ID: TTDS00449)
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Target Name |
Neutral endopeptidase (MME)
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Synonyms |
Skin fibroblast elastase; SFE; Neutral endopeptidase 24.11; Neprilysin; NEP protein; Enkephalinase; EPN; Common acute lymphocytic leukemia antigen; CD10; CALLA; Atriopeptidase
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Gene Name |
MME
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Target Type |
Clinical trial target
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[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.
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BioChemical Class |
Peptidase
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UniProt ID | |||||
EC Number |
EC 3.4.24.11
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Sequence |
MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW |
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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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