Target Information
Target General Infomation | |||||
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Target ID |
T06046
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Former ID |
TTDC00097
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Target Name |
Nitric-oxide synthase, endothelial
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Gene Name |
NOS3
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Synonyms |
CNOS; Constitutive NOS; EC-NOS; ENOS; Endothelial NOS; Endothelial nitric oxide synthase; NOS,type III; NOSIII; NOS3
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Target Type |
Clinical Trial
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Disease | Angina; Coronary artery disease [ICD9: 410-414, 413, 429.2; ICD10: I20, I20-I25] | ||||
Angina pectoris [ICD9: 413; ICD10: I20] | |||||
Brain injury [ICD10: S09.90] | |||||
Hypertension; Angina [ICD9: 401, 413; ICD10: I10-I16, I20] | |||||
Hypotension [ICD9: 458, 796.3; ICD10: I95] | |||||
Myocardial infarction [ICD9: 410; ICD10: I21, I22] | |||||
Pulmonary hypertension [ICD9: 416; ICD10: I27.0, I27.2] | |||||
Function |
Produces nitric oxide (no) which is implicated in vascular smooth muscle relaxation through a cgmp-mediated signal transduction pathway. No mediates vascular endothelial growth factor (vegf)-induced angiogenesis in coronary vessels and promotes blood clot.
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BioChemical Class |
Oxidoreductases acting on paired donors
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Target Validation |
T06046
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UniProt ID | |||||
EC Number |
EC 1.14.13.39
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Sequence |
MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDEPP ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT NSP |
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Structure |
4D1N; 4UCH; 4V3U; 1M9J; 1M9K; 1M9M; 1M9Q; 1M9R; 1NIW; 2LL7; 2MG5; 3EAH; 3NOS; 4D1O; 4D1P
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Drugs and Mode of Action | |||||
Drug(s) | Tilarginine acetate | Drug Info | Phase 3 | Myocardial infarction | [521644] |
ACCLAIM | Drug Info | Phase 2 | Angina; Coronary artery disease | [523027] | |
L-NAME | Drug Info | Phase 2 | Hypertension; Angina | [468266], [526685] | |
MTR105 | Drug Info | Phase 2 | Hypotension | [522040] | |
VAS-203 | Drug Info | Phase 2 | Brain injury | [548221] | |
Autologous cell based gene therapy | Drug Info | Phase 1 | Pulmonary hypertension | [534588] | |
L-NMMA | Drug Info | Discontinued in Phase 2 | Angina pectoris | [545605] | |
L-NIL | Drug Info | Terminated | Discovery agent | [546719] | |
Inhibitor | (5-Imino-[1,4]thiazepan-3-yl)-methanol | Drug Info | [527266] | ||
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine | Drug Info | [527502] | |||
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine | Drug Info | [527502] | |||
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin | Drug Info | [551393] | |||
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid | Drug Info | [534097] | |||
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid | Drug Info | [527266] | |||
1,2,4-Triazole-Carboxamidine | Drug Info | [551393] | |||
1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea | Drug Info | [528695] | |||
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea | Drug Info | [528695] | |||
2,4-Diamino-6-Phenyl-5,6,7,8,-Tetrahydropteridine | Drug Info | [551374] | |||
2-Amino-5-(N-nitro-guanidino)-pentanoic acid | Drug Info | [534097] | |||
2-Aminothiazoline | Drug Info | [551393] | |||
2-Methyl-2,4-Pentanediol | Drug Info | [551393] | |||
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
2-Propanol, Isopropanol | Drug Info | [551393] | |||
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
3-Bromo-1H-indazole-7-carbonitrile | Drug Info | [529494] | |||
3-bromo-7-nitro-1H-indazole | Drug Info | [529494] | |||
3-Bromo-7-Nitroindazole | Drug Info | [551393] | |||
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
3-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
3-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
4-Ethyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [526394] | |||
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
4-Ethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
4-Methyl-3,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [526394] | |||
4-Methyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [526394] | |||
4-methyl-6-propylpyridin-2-amine | Drug Info | [529745] | |||
4-Methyl-piperidin-(2E)-ylideneamine | Drug Info | [527502] | |||
4-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
4-methylpyridin-2-amine | Drug Info | [529745] | |||
5,6-Cyclic-Tetrahydropteridine | Drug Info | [551391] | |||
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
5-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
5-Nitroindazole | Drug Info | [551393] | |||
6-(2-Fluoropropyl)-4-methylpyridin-2-amine | Drug Info | [530039] | |||
6-(3-Fluoropropyl)-4-methylpyridin-2-amine | Drug Info | [530039] | |||
6-isobutyl-4-methylpyridin-2-amine | Drug Info | [530039] | |||
6-Nitroindazole | Drug Info | [551393] | |||
6s-5,6,7,8-Tetrahydrobiopterin | Drug Info | [551393] | |||
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine | Drug Info | [526140] | |||
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
7-Nitroindazole | Drug Info | [551393] | |||
7-Nitroindazole-2-Carboxamidine | Drug Info | [551374] | |||
Acetate Ion | Drug Info | [551393] | |||
AP-Cav | Drug Info | [535689] | |||
Azepan-(2Z)-ylideneamine | Drug Info | [526140] | |||
Cacodylate Ion | Drug Info | [551393] | |||
Ethylisothiourea | Drug Info | [551393] | |||
Heme | Drug Info | [551374] | |||
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine | Drug Info | [527210] | |||
Hydroxydimethylarsine Oxide | Drug Info | [551393] | |||
L-2-Amino-4-(Guanidinooxy)Butyric Acid | Drug Info | [551393] | |||
L-Homoarginine | Drug Info | [551393] | |||
L-NAME | Drug Info | [535004], [537587], [537590] | |||
L-NG-nitroarginine methyl ester | Drug Info | [535118] | |||
L-NIL | Drug Info | [529159] | |||
L-NIO | Drug Info | [529811] | |||
L-NMMA | Drug Info | [537513], [537560], [537561] | |||
L-Nw-nitroarginine | Drug Info | [531224] | |||
MTR105 | Drug Info | [529438] | |||
N,N-dimethylarginine | Drug Info | [551405] | |||
N-(3-(Aminomethyl)Benzyl)Acetamidine | Drug Info | [551374] | |||
N-(5-Amino-6-oxo-heptyl)-acetamidine | Drug Info | [527210] | |||
N-(Chlorophenyl)-N'-Hydroxyguanidine | Drug Info | [551374] | |||
N-omega-allyl-L-arginine | Drug Info | [529811] | |||
N-Omega-Hydroxy-L-Arginine | Drug Info | [551393] | |||
N-omega-propargyl-L-arginine | Drug Info | [529811] | |||
N1,N14-Bis((S-Methyl)Isothioureido)Tetradecane | Drug Info | [551393] | |||
N5-(1-iminobut-3-enyl)-L-ornithine | Drug Info | [529811] | |||
N5-(1-iminobutyl)-L-ornithine | Drug Info | [529811] | |||
N5-(1-iminopropyl)-L-ornithine | Drug Info | [529811] | |||
N5-Iminoethyl-L-Ornithine | Drug Info | [551391] | |||
Nitroarginine | Drug Info | [551396] | |||
Piperidin-(2E)-ylideneamine | Drug Info | [527502] | |||
Pyrrolidin-(2Z)-ylideneamine | Drug Info | [527210] | |||
S-(Dimethylarsenic)Cysteine | Drug Info | [551393] | |||
S-Ethyl-N-Phenyl-Isothiourea | Drug Info | [551374] | |||
S-Isopropyl-Isothiourea | Drug Info | [551393] | |||
Se-Ethyl-Isoselenourea | Drug Info | [551393] | |||
Thiazolidin-(2E)-ylideneamine | Drug Info | [527210] | |||
THIOCITRULLINE | Drug Info | [527563] | |||
VAS-203 | Drug Info | [532781] | |||
[1,3]Oxazinan-(2E)-ylideneamine | Drug Info | [534097] | |||
[1,3]Thiazinan-(2E)-ylideneamine | Drug Info | [534097] | |||
[1,4]Oxazepan-(3E)-ylideneamine | Drug Info | [527266] | |||
[1,4]Thiazepan-(3E)-ylideneamine | Drug Info | [527266] | |||
[1,4]Thiazepan-(5E)-ylideneamine | Drug Info | [527266] | |||
Stimulator | ACCLAIM | Drug Info | [550543] | ||
Modulator | Autologous cell based gene therapy | Drug Info | [526424] | ||
Tilarginine acetate | Drug Info | [528757] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
BioCyc Pathway | Citrulline-nitric oxide cycle | ||||
KEGG Pathway | Arginine and proline metabolism | ||||
Metabolic pathways | |||||
Calcium signaling pathway | |||||
cGMP-PKG signaling pathway | |||||
HIF-1 signaling pathway | |||||
Sphingolipid signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
VEGF signaling pathway | |||||
Platelet activation | |||||
Estrogen signaling pathway | |||||
Oxytocin signaling pathway | |||||
NetPath Pathway | Wnt Signaling Pathway | ||||
PANTHER Pathway | Angiogenesis | ||||
Endothelin signaling pathway | |||||
Interleukin signaling pathway | |||||
PI3 kinase pathway | |||||
VEGF signaling pathway | |||||
Pathway Interaction Database | Plasma membrane estrogen receptor signaling | ||||
Validated transcriptional targets of AP1 family members Fra1 and Fra2 | |||||
Angiopoietin receptor Tie2-mediated signaling | |||||
Thromboxane A2 receptor signaling | |||||
SHP2 signaling | |||||
VEGFR1 specific signals | |||||
Signaling events mediated by VEGFR1 and VEGFR2 | |||||
PAR1-mediated thrombin signaling events | |||||
Reactome | ROS production in response to bacteria | ||||
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation | |||||
eNOS activation | |||||
Nitric oxide stimulates guanylate cyclase | |||||
VEGFR2 mediated vascular permeability | |||||
WikiPathways | ACE Inhibitor Pathway | ||||
EGF/EGFR Signaling Pathway | |||||
Myometrial Relaxation and Contraction Pathways | |||||
JAK/STAT | |||||
Corticotropin-releasing hormone | |||||
AGE/RAGE pathway | |||||
Endothelin Pathways | |||||
Leptin signaling pathway | |||||
Effects of Nitric Oxide | |||||
Metabolism of nitric oxide | |||||
Angiogenesis | |||||
References | |||||
Ref 468266 | (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: 5213). | ||||
Ref 521644 | ClinicalTrials.gov (NCT00112281) A Study of the Safety and Efficacy of Nitric Oxide Reduction in Patients With Cardiogenic Shock After a Heart Attack. U.S. National Institutes of Health. | ||||
Ref 522040 | ClinicalTrials.gov (NCT00482287) Pharmacokinetics and Pharmacodynamics of MTR105 in Hypotensive Cardiac Surgery Patients. U.S. National Institutes of Health. | ||||
Ref 523027 | ClinicalTrials.gov (NCT01116427) A Cooperative Clinical Study of Abatacept in Multiple Sclerosis. U.S. National Institutes of Health. | ||||
Ref 526685 | Inhibition of nitric oxide synthase by L-NAME speeds phase II pulmonary .VO2 kinetics in the transition to moderate-intensity exercise in man. J Physiol. 2003 Oct 1;552(Pt 1):265-72. Epub 2003 Aug 1. | ||||
Ref 534588 | A Phase I study of the transplantation of genetically marked autologous bone marrow stromal cells. Hum Gene Ther. 1998 Mar 1;9(4):591-600. | ||||
Ref 545605 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003882) | ||||
Ref 526140 | Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. | ||||
Ref 526394 | Bioorg Med Chem Lett. 2002 Sep 2;12(17):2291-4.Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines. | ||||
Ref 526424 | Feasibility of using autologous transplantation to evaluate hematopoietic stem cell-based gene therapy strategies in transgenic mouse models of human disease. Mol Ther. 2002 Sep;6(3):422-8. | ||||
Ref 527210 | Bioorg Med Chem Lett. 2004 Sep 6;14(17):4539-44.Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase. | ||||
Ref 527266 | Bioorg Med Chem Lett. 2004 Dec 6;14(23):5907-11.Synthesis of analogs of (1,4)-3- and 5-imino oxazepane, thiazepane, and diazepane as inhibitors of nitric oxide synthases. | ||||
Ref 527502 | Bioorg Med Chem Lett. 2005 Apr 15;15(8):1997-2001.Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase. | ||||
Ref 527563 | Bioorg Med Chem Lett. 2005 Jun 2;15(11):2881-5. Epub 2005 Apr 25.Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes. | ||||
Ref 528695 | Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4. Epub 2007 Feb 8.Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. | ||||
Ref 528757 | Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA. 2007 Apr 18;297(15):1657-66. Epub 2007 Mar 26. | ||||
Ref 529159 | Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43. Epub 2007 Oct 25.Discovery of a series of aminopiperidines as novel iNOS inhibitors. | ||||
Ref 529438 | Nitric oxide synthase inhibitor (MTR-105) during open-heart surgery. A pilot double-blind placebo-controlled study of hemodynamic effects and safety. Cardiology. 2008;111(3):181-7. | ||||
Ref 529494 | Bioorg Med Chem. 2008 Jun 1;16(11):5962-73. Epub 2008 Apr 26.Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile. | ||||
Ref 529745 | Nat Chem Biol. 2008 Nov;4(11):700-7. Epub 2008 Oct 12.Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. | ||||
Ref 529811 | Bioorg Med Chem. 2008 Dec 15;16(24):10205-9. Epub 2008 Oct 29.Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads. | ||||
Ref 530039 | J Med Chem. 2009 Apr 23;52(8):2443-53.Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine as a potential PET tracer for inducible nitric oxide synthase. | ||||
Ref 531224 | J Med Chem. 2010 Nov 11;53(21):7804-24.Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives. | ||||
Ref 532781 | Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). J Neurotrauma. 2014 Oct 1;31(19):1599-606. | ||||
Ref 534097 | J Med Chem. 1996 Feb 2;39(3):669-72.2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. | ||||
Ref 535004 | L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway. Mediators Inflamm. 2000;9(1):25-30. | ||||
Ref 535118 | COX-2 and iNOS, good targets for chemoprevention of colon cancer. Biofactors. 2000;12(1-4):129-33. | ||||
Ref 535689 | Endothelial nitric oxide synthase: the Cinderella of inflammation? Trends Pharmacol Sci. 2003 Feb;24(2):91-5. | ||||
Ref 537513 | Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs. Intensive Care Med. 2009 Jun 24. | ||||
Ref 537560 | Gonadal hormones decrease temporomandibular joint kappa-mediated antinociception through a down-regulation in the expression of kappa opioid receptors in the trigeminal ganglia. Eur J Pharmacol. 2009Jun 28. | ||||
Ref 537561 | Gender is related to alterations of renal endothelial function in type 2 diabetes. Nephrol Dial Transplant. 2009 Jun 30. | ||||
Ref 537587 | Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contractility. Acta Physiol (Oxf). 2009 Jul 6. | ||||
Ref 537590 | Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection. Vascul Pharmacol. 2009 Jul 5. | ||||
Ref 551391 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January |
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