Target Information

Target General Infomation
Target ID
T05409
Former ID
TTDS00449
Target Name
Neutral endopeptidase
Gene Name
MME
Synonyms
CALLA; CD10; Common acute lymphocytic leukemia antigen; Enkephalinase; NEP; Neutral endopeptidase; Neutral endopeptidase 24.11; MME
Target Type
Clinical Trial
Disease Acute decompensated heart failure; Renal dysfunction [ICD9: 428, 428.0, 584, 585; ICD10: I50, N17-N19]
Brain injury [ICD10: S09.90]
Cardiovascular disorder [ICD10: I00-I99]
Chronic pain [ICD9: 338.2,780; ICD10: R52.1-R52.2, G89]
Female sexual dysfunction [ICD9: 302.7; ICD10: F52]
Hypertension [ICD9: 401; ICD10: I10-I16]
Heart failure [ICD9: 428; ICD10: I50]
Hypertension; Renal failure; Heart failure; Diabetic nephropathy [ICD9: 250, 401, 428, 580-599, 584, 585; ICD10: E08-E13, I10-I16, I50, N00-N29, N17, N18, N19]
Hypotension [ICD9: 458, 796.3; ICD10: I95]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Function
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of atrial natriuretic factor (ANF) (PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573).
BioChemical Class
Peptidase
Target Validation
T05409
UniProt ID
P08473
EC Number
EC 3.4.24.11
Sequence
MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD
VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA
SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE
ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY
NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT
KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME
NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI
GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA
VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR
AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII
GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW
Drugs and Mode of Action
Drug(s) LCZ696 Drug Info Approved Heart failure [1]
Candoxatril Drug Info Phase 3 Hypertension [2], [3]
Sampatrilat Drug Info Phase 2 Hypotension [4]
SLV 306 Drug Info Phase 2 Acute decompensated heart failure; Renal dysfunction [5], [6]
SLV-334 Drug Info Phase 2 Brain injury [7]
Debio 0827 Drug Info Phase 1 Chronic pain [8]
GW-796406 Drug Info Phase 1 Hypotension [9]
Pfizer 4 Drug Info Phase 1 Female sexual dysfunction [10]
SLV-338 Drug Info Phase 1 Cardiovascular disorder [11]
Ilepatril Drug Info Discontinued in Phase 2/3 Hypertension; Renal failure; Heart failure; Diabetic nephropathy [12]
Fasidotril Drug Info Discontinued in Phase 2 Hypotension [13], [14]
Gemopatrilat Drug Info Discontinued in Phase 2 Hypotension [15]
M-100240 Drug Info Discontinued in Phase 2 Hypotension [16]
SCH-32615 Drug Info Discontinued in Phase 2 Pain [17]
SCH-42495 Drug Info Discontinued in Phase 2 Hypotension [18]
Candoxatrilat Drug Info Discontinued in Phase 1 Heart failure [19], [20]
GSK 796406 Drug Info Discontinued in Phase 1 Hypertension [21]
BMS-182657 Drug Info Terminated Cardiovascular disorder [22]
CGS-26303 Drug Info Terminated Discovery agent [23]
CGS-30440 Drug Info Terminated Hypertension [24]
GW-660511 Drug Info Terminated Hypertension [25]
Omapatrilat Drug Info Terminated Hypertension [26]
SCH-54470 Drug Info Terminated Discovery agent [27]
SQ-26332 Drug Info Terminated Discovery agent [28]
Inhibitor 9-Mercaptomethyl-10-oxo-azecane-2-carboxylic acid Drug Info [29]
Candoxatril Drug Info [30], [31]
Candoxatrilat Drug Info [32], [7]
CGS-26303 Drug Info [33]
CGS-314447 Drug Info [33]
compound 1b Drug Info [34]
Debio 0827 Drug Info [8]
fasidotrilat Drug Info [35]
GSK 796406 Drug Info [36]
LBQ657 Drug Info [37]
Pfizer 4 Drug Info [10]
Phosphoramidon Drug Info [38]
SCH-32615 Drug Info [39], [7]
SCH-42495 Drug Info [7], [40]
SCH-54470 Drug Info [41]
SQ-26332 Drug Info [42]
Thiorphan Drug Info [43]
[2(R,S)-2-Sulfanylheptanoyl]-Phe-Ala Drug Info [44]
Modulator BMS-182657 Drug Info [22]
CGS-30440 Drug Info [24]
Fasidotril Drug Info
Gemopatrilat Drug Info
GW-660511 Drug Info [25]
GW-796406 Drug Info [36]
Ilepatril Drug Info [12]
LCZ696 Drug Info [1]
M-100240 Drug Info
Omapatrilat Drug Info [26]
RB-105 Drug Info
Sampatrilat Drug Info [4]
SLV 306 Drug Info [7], [45]
SLV-334 Drug Info
SLV-338 Drug Info [11]
Pathways
KEGG Pathway Renin-angiotensin system
Hematopoietic cell lineage
Protein digestion and absorption
Alzheimer&#039
s disease
NetPath Pathway EGFR1 Signaling Pathway
TGF_beta_Receptor Signaling Pathway
Reactome Metabolism of Angiotensinogen to Angiotensins
WikiPathways Metabolism of Angiotensinogen to Angiotensins
Primary Focal Segmental Glomerulosclerosis FSGS
Alzheimers Disease
References
REF 12014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
REF 2(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 3Drug information of Candoxatril, 2008. eduDrugs.
REF 4Sustained 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 5ClinicalTrials.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 6(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 7The 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 8Clinical pipeline report, company report or official report of Debiopharm (2011).
REF 9Mechanism 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. Epub 2005 Sep 6.
REF 10Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. Epub 2007 Aug 27.
REF 11Renoprotective 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 12Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension. Curr Opin Investig Drugs. 2008 Mar;9(3):301-9.
REF 13(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 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003997)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009581)
REF 16Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002832)
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002402)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002070)
REF 19(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 20Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001740)
REF 21Mechanism of Vasopeptidase Inhibitor-Induced Plasma Extravasation: Comparison of Omapatrilat and the Novel Neutral Endopeptidase 24.11/Angiotensin-Converting Enzyme Inhibitor GW796406. JPET December 2005 vol. 315 no. 3 1306-1313.
REF 22Cardiovascular 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 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005936)
REF 24Antihypertensive 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 25The 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 26Omapatrilat, 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 27Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007872)
REF 28Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000347)
REF 29J Med Chem. 1993 Nov 26;36(24):3821-8.Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor.
REF 30Dual 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 31Neutral 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 32Candoxatril, 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 33Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11, Bioorg. Med. Chem. Lett. 7(8):1059-1064 (1997).
REF 34Thiol-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. Epub 2007 Nov 19.
REF 35Modelling 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 36Mechanism 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(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 38Neprilysin, a novel target for ultraviolet B regulation of melanogenesis via melanocortins. J Invest Dermatol. 2000 Sep;115(3):381-7.
REF 39The 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 40Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension. Hypertension. 1993 Jul;22(1):119-26.
REF 41J Med Chem. 2010 Jan 14;53(1):208-20.Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors.
REF 42J Med Chem. 2005 Oct 20;48(21):6523-43.Designed multiple ligands. An emerging drug discovery paradigm.
REF 43Thiorphan enhances bradykinin-induced vascular relaxation in hypoxic/hyperkalaemic porcine coronary artery. J Pharm Pharmacol. 2003 Mar;55(3):339-45.
REF 44How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 45Effect 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.

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