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]
Chronic pain [ICD9: 338.2,780; ICD10: R52.1-R52.2, G89]
Cardiovascular disorder [ICD10: I00-I99]
Female sexual dysfunction [ICD9: 302.7; ICD10: F52]
Hypotension [ICD9: 458, 796.3; ICD10: I95]
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]
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 [533123]
Candoxatril Drug Info Phase 3 Hypertension [541627], [550674]
Sampatrilat Drug Info Phase 2 Hypotension [525516]
SLV 306 Drug Info Phase 2 Acute decompensated heart failure; Renal dysfunction [521684], [541643]
SLV-334 Drug Info Phase 2 Brain injury [531869]
Debio 0827 Drug Info Phase 1 Chronic pain [550597]
GW-796406 Drug Info Phase 1 Hypotension [527730]
Pfizer 4 Drug Info Phase 1 Female sexual dysfunction [536493]
SLV-338 Drug Info Phase 1 Cardiovascular disorder [531611]
Ilepatril Drug Info Discontinued in Phase 2/3 Hypertension; Renal failure; Heart failure; Diabetic nephropathy [536642]
Fasidotril Drug Info Discontinued in Phase 2 Hypotension [541638], [545632]
Gemopatrilat Drug Info Discontinued in Phase 2 Hypotension [546675]
M-100240 Drug Info Discontinued in Phase 2 Hypotension [545322]
SCH-32615 Drug Info Discontinued in Phase 2 Pain [545185]
SCH-42495 Drug Info Discontinued in Phase 2 Hypotension [545085]
Candoxatrilat Drug Info Discontinued in Phase 1 Heart failure [541626], [544971]
GSK 796406 Drug Info Discontinued in Phase 1 Hypertension [549953]
BMS-182657 Drug Info Terminated Cardiovascular disorder [533583]
CGS-26303 Drug Info Terminated Discovery agent [546022]
CGS-30440 Drug Info Terminated Hypertension [534574]
GW-660511 Drug Info Terminated Hypertension [525698]
Omapatrilat Drug Info Terminated Hypertension [526007]
SCH-54470 Drug Info Terminated Discovery agent [546391]
SQ-26332 Drug Info Terminated Discovery agent [544625]
Inhibitor 9-Mercaptomethyl-10-oxo-azecane-2-carboxylic acid Drug Info [533959]
Candoxatril Drug Info [536226], [536673]
Candoxatrilat Drug Info [526732], [531869]
CGS-26303 Drug Info [551340]
CGS-314447 Drug Info [551340]
compound 1b Drug Info [529216]
Debio 0827 Drug Info [550597]
fasidotrilat Drug Info [528271]
GSK 796406 Drug Info [549997]
LBQ657 Drug Info [543446]
Pfizer 4 Drug Info [536493]
Phosphoramidon Drug Info [535034]
SCH-32615 Drug Info [531695], [531869]
SCH-42495 Drug Info [531869], [534015]
SCH-54470 Drug Info [530505]
SQ-26332 Drug Info [527799]
Thiorphan Drug Info [535731]
[2(R,S)-2-Sulfanylheptanoyl]-Phe-Ala Drug Info [551393]
Modulator BMS-182657 Drug Info [533583]
CGS-30440 Drug Info [534574]
Fasidotril Drug Info
Gemopatrilat Drug Info
GW-660511 Drug Info [525698]
GW-796406 Drug Info [549997]
Ilepatril Drug Info [536642]
LCZ696 Drug Info [533123]
M-100240 Drug Info
Omapatrilat Drug Info [526007]
RB-105 Drug Info
Sampatrilat Drug Info [525516]
SLV 306 Drug Info [531869], [535988]
SLV-334 Drug Info
SLV-338 Drug Info [531611]
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 521684ClinicalTrials.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 525516Sustained 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 525698The 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 526007Omapatrilat, 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 527730Mechanism 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 531611Renoprotective 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 531869The 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 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 533583Cardiovascular 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 534574Antihypertensive 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 536493Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. Epub 2007 Aug 27.
Ref 536642Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension. Curr Opin Investig Drugs. 2008 Mar;9(3):301-9.
Ref 541626(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 541627(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 541638(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 541643(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 544625Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000347)
Ref 544971Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001740)
Ref 545085Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002070)
Ref 545185Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002402)
Ref 545322Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002832)
Ref 545632Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003997)
Ref 546022Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005936)
Ref 546391Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007872)
Ref 546675Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009581)
Ref 549953Mechanism 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 550597Clinical pipeline report, company report or official report of Debiopharm (2011).
Ref 550674Drug information of Candoxatril, 2008. eduDrugs.
Ref 525516Sustained 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 525698The 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 526007Omapatrilat, 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 526732Candoxatril, 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 527799J Med Chem. 2005 Oct 20;48(21):6523-43.Designed multiple ligands. An emerging drug discovery paradigm.
Ref 528271Modelling 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 529216Thiol-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 530505J 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 531611Renoprotective 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 531695The 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 531869The 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 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 533583Cardiovascular 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 533959J Med Chem. 1993 Nov 26;36(24):3821-8.Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor.
Ref 534015Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension. Hypertension. 1993 Jul;22(1):119-26.
Ref 534574Antihypertensive 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 535034Neprilysin, a novel target for ultraviolet B regulation of melanogenesis via melanocortins. J Invest Dermatol. 2000 Sep;115(3):381-7.
Ref 535731Thiorphan enhances bradykinin-induced vascular relaxation in hypoxic/hyperkalaemic porcine coronary artery. J Pharm Pharmacol. 2003 Mar;55(3):339-45.
Ref 535988Effect 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 536226Dual 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 536493Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. Epub 2007 Aug 27.
Ref 536642Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension. Curr Opin Investig Drugs. 2008 Mar;9(3):301-9.
Ref 536673Neutral 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 543446(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 549997Mechanism 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 550597Clinical pipeline report, company report or official report of Debiopharm (2011).
Ref 551340Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11, Bioorg. Med. Chem. Lett. 7(8):1059-1064 (1997).
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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