Target Information

Target General Infomation
Target ID
T06046
Former ID
TTDC00097
Target Name
Nitric-oxide synthase, endothelial
Gene Name
NOS3
Synonyms
CNOS; Constitutive NOS; EC-NOS; ENOS; Endothelial NOS; Endothelial nitric oxide synthase; NOS,type III; NOSIII; NOS3
Target Type
Clinical Trial
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]
Hypotension [ICD9: 458, 796.3; ICD10: I95]
Hypertension; Angina [ICD9: 401, 413; ICD10: I10-I16, I20]
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.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T06046
UniProt ID
P29474
EC Number
EC 1.14.13.39
Sequence
MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP
EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN
APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD
FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDEPP
ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST
EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH
HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW
KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR
LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS
PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF
CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA
RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL
VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP
PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY
EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL
AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP
FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE
PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD
EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT
NSP
Structure
4D1N; 4UCH; 4V3U; 1M9J; 1M9K; 1M9M; 1M9Q; 1M9R; 1NIW; 2LL7; 2MG5; 3EAH; 3NOS; 4D1O; 4D1P
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 521644ClinicalTrials.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 522040ClinicalTrials.gov (NCT00482287) Pharmacokinetics and Pharmacodynamics of MTR105 in Hypotensive Cardiac Surgery Patients. U.S. National Institutes of Health.
Ref 523027ClinicalTrials.gov (NCT01116427) A Cooperative Clinical Study of Abatacept in Multiple Sclerosis. U.S. National Institutes of Health.
Ref 526685Inhibition 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 534588A 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 545605Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003882)
Ref 546719Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009876)
Ref 548221Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023224)
Ref 526140Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase.
Ref 526394Bioorg 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 526424Feasibility 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 527210Bioorg 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 527266Bioorg 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 527502Bioorg 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 527563Bioorg 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 528695Bioorg 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 528757Effect 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 529159Bioorg 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 529438Nitric 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 529494Bioorg 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 529745Nat 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 529811Bioorg 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 530039J 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 531224J 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 532781Nitric 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 534097J 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 535004L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway. Mediators Inflamm. 2000;9(1):25-30.
Ref 535118COX-2 and iNOS, good targets for chemoprevention of colon cancer. Biofactors. 2000;12(1-4):129-33.
Ref 535689Endothelial nitric oxide synthase: the Cinderella of inflammation? Trends Pharmacol Sci. 2003 Feb;24(2):91-5.
Ref 537513Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs. Intensive Care Med. 2009 Jun 24.
Ref 537560Gonadal 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 537561Gender is related to alterations of renal endothelial function in type 2 diabetes. Nephrol Dial Transplant. 2009 Jun 30.
Ref 537587Enhanced 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 537590Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection. Vascul Pharmacol. 2009 Jul 5.
Ref 550543CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551391DrugBank 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
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551396Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry. 2001 Nov 13;40(45):13448-55.
Ref 551405van Guldener C, Nanayakkara PW, Stehouwer CD: Review: Homocysteine and asymmetric dimethylarginine (<span class="caps">ADMA</span>): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med. 2007 Oct 15;.

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