Target Information

Target General Infomation
Target ID
T40332
Former ID
TTDS00448
Target Name
Leukocyte elastase
Gene Name
ELANE
Synonyms
Bone marrow serine protease; Medullasin; Neutrophil elastase; PMN elastase; ELANE
Target Type
Clinical Trial
Disease Acute lung injury [ICD9: 518; ICD10: J80]
Acute lung injury; Acute respiratory distress syndrome; Cystic fibrosis [ICD9: 277.0, 518.5, 518.82, 709.2; ICD10: E84, J80, L90.5]
Acute lung injury; Acute respiratory distress syndrome [ICD9: 518.5, 518.82; ICD10: J80]
Atopic dermatitis [ICD9: 691.8, 692.9; ICD10: L00-L99]
Asthma; Chronic obstructive pulmonary disease [ICD9: 490-492, 493, 494-496; ICD10: J40-J44, J47, J45]
Bronchiectasis [ICD9: 494, 748.61; ICD10: J47, Q33.4]
Cystic fibrosis [ICD9: 277; ICD10: E84]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Mucolytic [ICD10: J00-J99]
Myocardial infarction [ICD9: 410; ICD10: I21, I22]
Pulmonary emphysema [ICD10: J43]
Pulmonary disease [ICD9: 460-519; ICD10: J00-J99]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Septic shock; Myocardial ischaemia-reperfusion injury; Acute respiratory distress syndrome [ICD9: 492, 518.5, 518.82, 785.52; ICD10: A41.9, J43, J80]
Function
Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.
BioChemical Class
Peptidase
Target Validation
T40332
UniProt ID
P08246
EC Number
EC 3.4.21.37
Sequence
MTLGRRLACLFLACVLPALLLGGTALASEIVGGRRARPHAWPFMVSLQLRGGHFCGATLI
APNFVMSAAHCVANVNVRAVRVVLGAHNLSRREPTRQVFAVQRIFENGYDPVNLLNDIVI
LQLNGSATINANVQVAQLPAQGRRLGNGVQCLAMGWGLLGRNRGIASVLQELNVTVVTSL
CRRSNVCTLVRGRQAGVCFGDSGSPLVCNGLIHGIASFVRGGCASGLYPDAFAPVAQFVN
WIDSIIQRSEDNPCPHPRDPDPASRTH
Drugs and Mode of Action
Drug(s) Sivelestat Drug Info Phase 4 Discovery agent [521724], [541582]
Sivelestat sodium hydrate Drug Info Phase 4 Acute lung injury; Acute respiratory distress syndrome [536361]
BAY 85-8501 Drug Info Phase 2 Bronchiectasis [549458]
DX-890 Drug Info Phase 2 Acute lung injury; Acute respiratory distress syndrome; Cystic fibrosis [522003]
L-694,458 Drug Info Phase 2 Cystic fibrosis [551850]
Tiprelestat Drug Info Phase 2 Myocardial infarction [548073]
AZD-9819 Drug Info Phase 1 Chronic obstructive pulmonary disease [523120]
MR-889 Drug Info Discontinued in Phase 3 Mucolytic [545562]
AZD9668 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [541611], [548573]
CE-1037 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [545583]
Dermolastin Drug Info Discontinued in Phase 2 Atopic dermatitis [547642]
FK-706 Drug Info Discontinued in Phase 2 Pulmonary emphysema [546595]
ZD-8321 Drug Info Discontinued in Phase 2 Acute lung injury [546286]
AE-3763 Drug Info Discontinued in Phase 1 Chronic obstructive pulmonary disease [547367]
AZD-6553 Drug Info Discontinued in Phase 1 Chronic obstructive pulmonary disease [549132]
GW-311616 Drug Info Discontinued in Phase 1 Discovery agent [546572]
ONO-6818 Drug Info Discontinued in Phase 1 Chronic obstructive pulmonary disease [547077]
ZD-0892 Drug Info Discontinued in Phase 1 Chronic obstructive pulmonary disease [546659]
FR-901277 Drug Info Terminated Discovery agent [546457]
FR-901451 Drug Info Terminated Discovery agent [546253]
Mdl 101,146 Drug Info Terminated Inflammatory disease [546375]
SR-26831 Drug Info Terminated Rheumatoid arthritis [544831]
Inhibitor (1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info [529037]
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone Drug Info [529037]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info [529037]
(3-nitro-1H-pyrazol-1-yl)(phenyl)methanone Drug Info [529037]
(4-bromo-1H-pyrazol-1-yl)(m-tolyl)methanone Drug Info [529037]
(4-bromo-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info [529037]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info [529037]
(4-chloro-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info [529037]
(4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info [529037]
(4-nitro-1H-pyrazol-1-yl)(phenyl)methanone Drug Info [529037]
1-(3,3-Dimethyl-2-oxo-butyl)-1H-indole-2,3-dione Drug Info [525916]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide Drug Info [529037]
1-benzyl-3,3-diethylazetidine-2,4-dione Drug Info [530511]
1-benzyl-3,3-dimethylazetidine-2,4-dione Drug Info [530511]
2-methylbut-3-yn-2-yl 4-methoxybenzoate Drug Info [529037]
3,3-Diethyl-1-(pyridin-3-yl)azetidine-2,4-dione Drug Info [530511]
3,3-Diethyl-1-o-tolylazetidine-2,4-dione Drug Info [530511]
3,3-diethyl-1-phenylazetidine-2,4-dione Drug Info [530511]
3,4-dichloroisocoumarin Drug Info [528555]
3-Benzyl-3-ethyl-1-phenylazetidine-2,4-dione Drug Info [530511]
3-Benzyl-3-methyl-1-phenylazetidine-2,4-dione Drug Info [530511]
3-butyl-3-ethyl-1-phenylazetidine-2,4-dione Drug Info [530511]
3-Decanoyl-4-hydroxy-6-nonyl-pyran-2-one Drug Info [533472]
3-Ethyl-3-isobutyl-1-phenylazetidine-2,4-dione Drug Info [530511]
4-Hydroxy-3-nonanoyl-6-octyl-pyran-2-one Drug Info [533472]
4-methoxy-N'-(2-phenylacetyl)benzohydrazide Drug Info [529037]
6-Heptyl-4-hydroxy-3-octanoyl-pyran-2-one Drug Info [533472]
Ac-Ala-Pro-Val-(2-benzoxazole) Drug Info [529193]
ADC-7828 Drug Info [543602]
AE-3763 Drug Info [535494]
AX-9657 Drug Info [543602]
AZD-6553 Drug Info [549133]
AZD-9819 Drug Info [533294]
AZD9668 Drug Info [550288]
Bornyl (3,4,5-trihydroxy)-cinnamate Drug Info [529218]
Cbz-Val-Pro-Val-(2-benzoxazole) Drug Info [529193]
CE-1037 Drug Info [535494]
compound 10f Drug Info [532680]
compound 10l Drug Info [532680]
compound 4g Drug Info [531910]
Dermolastin Drug Info [536190], [536840], [537435], [551533]
DX-890 Drug Info [536500]
E-6-O-p-methoxycinnamoyl scandoside methyl ester Drug Info [530569]
EPIGALOCATECHIN GALLATE Drug Info [530569]
FK-706 Drug Info [535494]
FR-901277 Drug Info [528807]
FR-901451 Drug Info [528807]
Fucose Drug Info [551393]
GW-311616 Drug Info [535494]
ICI 200,355 Drug Info [534889], [534999], [537654], [537940], [538031]
ICI 200,880 Drug Info [535494], [537900]
L-658,758 Drug Info [538111]
L-694,458 Drug Info [535494]
Mdl 101,146 Drug Info [551393]
MR-889 Drug Info [535494]
N,N-bis(cyanomethyl)-3,4-dimethoxybenzamide Drug Info [529037]
ONO-6818 Drug Info [535494]
POL-6014 Drug Info [543602]
Sivelestat Drug Info [537032]
Sivelestat sodium hydrate Drug Info [536500]
TEI-8362 Drug Info [535494]
WIN-63395 Drug Info [551308]
ZD-0892 Drug Info [535494]
ZD-8321 Drug Info [535494]
ZK-814048 Drug Info [528872]
Modulator BAY 85-8501 Drug Info [533269]
SR-26831 Drug Info [528753]
Tiprelestat Drug Info
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Transcriptional misregulation in cancer
Systemic lupus erythematosus
Pathway Interaction Database Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
C-MYB transcription factor network
Reactome Collagen degradation
Degradation of the extracellular matrix
Activation of Matrix Metalloproteinases
WikiPathways Cytodifferentiation (Part 3 of 3)
Human Complement System
Degradation of collagen
References
Ref 521724ClinicalTrials.gov (NCT00219375) Study of Sivelestat Sodium Hydrate in Acute Lung Injury (ALI) Associated With Systemic Inflammatory Response Syndrome (SIRS) in Japan. U.S. National Institutes of Health.
Ref 522003ClinicalTrials.gov (NCT00455767) Safety and Efficacy Study of Depelestat in Acute Respiratory Distress Syndrome (ARDS) Patients. U.S. National Institutes of Health.
Ref 523120ClinicalTrials.gov (NCT01166698) Single Centre, Double-blind, Single and Multiple Ascending Inhaled Doses of AZD9819 in Healthy Subjects. U.S. National Institutes of Health.
Ref 536361Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
Ref 541582(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: 6441).
Ref 541611(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: 6476).
Ref 544831Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001260)
Ref 545562Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003709)
Ref 545583Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003784)
Ref 546253Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007127)
Ref 546286Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007250)
Ref 546375Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007771)
Ref 546457Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008229)
Ref 546572Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008997)
Ref 546595Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009108)
Ref 546659Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009537)
Ref 547077Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012873)
Ref 547367Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015539)
Ref 547642Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018071)
Ref 548073Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021706)
Ref 548573Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026715)
Ref 549132Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032703)
Ref 549458Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037600)
Ref 551850New Drugs and Targets for Asthma and COPD, T.T. Hansel, ??.J. Barnes. Page(248).
Ref 525916Bioorg Med Chem Lett. 2000 Nov 20;10(22):2501-4.Parallel synthesis of isatin-based serine protease inhibitors.
Ref 528555Antimicrob Agents Chemother. 2007 Feb;51(2):543-50. Epub 2006 Dec 4.Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131.
Ref 528753Biochemical and pharmacological activities of SR 26831, a potent and selective elastase inhibitor. J Pharmacol Exp Ther. 1992 Feb;260(2):809-16.
Ref 528807Bioorg Med Chem. 2007 Jul 1;15(13):4618-28. Epub 2007 Apr 3.Resisting degradation by human elastase: commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds.
Ref 528872J Med Chem. 2007 Jun 28;50(13):2967-80. Epub 2007 May 31.Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors.
Ref 529037J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
Ref 529193Bioorg Med Chem. 2008 Feb 15;16(4):1562-95. Epub 2007 Nov 6.Inhibitors of proteases and amide hydrolases that employ an alpha-ketoheterocycle as a key enabling functionality.
Ref 529218Bioorg Med Chem. 2008 Mar 1;16(5):2385-90. Epub 2007 Nov 29.Bornyl (3,4,5-trihydroxy)-cinnamate--an optimized human neutrophil elastase inhibitor designed by free energy calculations.
Ref 530511J Med Chem. 2010 Jan 14;53(1):241-53.4-Oxo-beta-lactams (azetidine-2,4-diones) are potent and selective inhibitors of human leukocyte elastase.
Ref 530569Bioorg Med Chem Lett. 2010 Jan 15;20(2):513-5. Epub 2009 Nov 26.Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Ref 531910N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases. Bioorg Med Chem Lett. 2012 Jun 15;22(12):3993-7.
Ref 532680Synthesis and evaluation of 2-(1H-indol-3-yl)-4-phenylquinolines as inhibitors of cholesterol esterase. Bioorg Med Chem Lett. 2014 Mar 15;24(6):1545-9.
Ref 533269Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY??5-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases. ChemMedChem. 2015 Jul;10(7):1163-73.
Ref 533294Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples. Drug Metab Dispos. 2015 Oct;43(10):1441-9.
Ref 533472J Med Chem. 1987 Jun;30(6):1017-23.Inhibition of human sputum elastase by substituted 2-pyrones.
Ref 534889LTB(4)-induced nasal gland serous cell secretion mediated by neutrophil elastase. Am J Respir Crit Care Med. 1999 Aug;160(2):411-4.
Ref 534999Role of neutrophil elastase in hypersecretion in asthma. Eur Respir J. 1999 Jan;13(1):190-6.
Ref 535494Neutrophil elastase inhibitors as treatment for COPD. Expert Opin Investig Drugs. 2002 Jul;11(7):965-80.
Ref 536190rAAt (inhaled) Arriva/Hyland Immuno. Curr Opin Mol Ther. 2006 Feb;8(1):76-82.
Ref 536500Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome. Expert Opin Emerg Drugs. 2007 Sep;12(3):461-77.
Ref 536574Therapeutic applications of aptamers. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60.
Ref 536840Bioreactor strategies for improving production yield and functionality of a recombinant human protein in transgenic tobacco cell cultures. Biotechnol Bioeng. 2009 Feb 1;102(2):508-20.
Ref 537032Neutrophil elastase inhibitor (sivelestat) reduces the levels of inflammatory mediators by inhibiting NF-kB. Inflamm Res. 2009 Apr;58(4):198-203.
Ref 537435Optimization of the bioprocessing conditions for scale-up of transient production of a heterologous protein in plants using a chemically inducible viral amplicon expression system. Biotechnol Prog. 2009 May-Jun;25(3):722-34.
Ref 537654Inhibition of human neutrophil elastase by ICI 200,355. Eur J Pharmacol. 1991 Feb 7;193(2):153-8.
Ref 537900Neutrophil elastase inhibitor ICI 200,880 protects against attenuation of coronary flow reserve and myocardial dysfunction following temporary coronary artery occlusion in the dog. Cardiovasc Res. 1994 Jul;28(7):947-56.
Ref 537940Effect of a synthetic leukocyte elastase inhibitor on thrombin-induced pulmonary edema in the rat. Exp Lung Res. 1993 Mar-Apr;19(2):125-35.
Ref 538031Elastase contributes to antigen-induced mucociliary dysfunction in ovine airways. Am J Respir Crit Care Med. 1997 May;155(5):1522-8.
Ref 538111Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol. 1998 Aug;275(2 Pt 2):H385-92.
Ref 543602(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: 2358).
Ref 549133Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032703)
Ref 550288Clinical pipeline report, company report or official report of AstraZeneca (2009).
Ref 551308A comparative SAR and computer modeling study of benzisothiazolone, mechanism-based inhibitors with porcine pancreatic and human leukocyte elastase, Bioorg. Med. Chem. Lett. 6(24):2941-2946 (1996).
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551533Arriva-ProMetic recombinant alpha 1-antitrypsin (rAAT) moves into the clinic for dermatology applications. ProMetic Life Sciences. 2009.

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