Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
   

 

TTD Target ID: TTDC00097

Target Information
NameNitric-oxide synthase, endothelial    
Type of targetClinical trial target    
SynonymsCNOS    
Constitutive NOS    
EC-NOS    
ENOS    
Endothelial NOS    
Endothelial nitric oxide synthase    
NOS, type III    
NOSIII    
DiseaseAngina
[ICD9: 413   ICD10: I20]
[1][2][3]
Cardiovascular disease, unspecified
[ICD9: 390-459   ICD10: I00-I99]
[4]
Colon cancer
[ICD9: 153, 154   ICD10: C18-C21]
[5]
Coronary Artery Disease
[ICD9: 410-414, 429.2   ICD10: I20-I25]
[6]
Helminth infection
[ICD9: 001-139   ICD10: A00-B99]
[7]
Hypertension, Angina
[ICD9: 401, 413   ICD10: I10, I11, I12, I13, I15, I20]
[8][9][10]
Inflammation[11]
Schizophrenia
[ICD9: 295   ICD10: F20]
[12]
Sepsis
[ICD9: 995.91   ICD10: A40, A41]
[13]
Drug(s)ACCLAIMPhase IIIAngina, Coronary Artery Disease[6]
L-NMMAPhase IIIAngina[1][2][3]
L-NAMEPhase II/IIIHypertension, Angina[8][9][10]
BioChemical ClassOxidoreductases acting on paired donors    
EC NumberEC 1.14.13.39
UniProt IDP29474
PDB Structure1M9J; 1M9K; 1M9M; 1M9Q; 1M9R; 2LL7; 3EAH; 3NOS.    
FunctionProduces 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.    
SequenceMGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDEPP ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT NSP
Related US Patent6,225,305
6,297,276
6,344,473
6,344,483
6,355,689
6,362,195
6,372,733
6,391,887
6,403,830
6,410,542
6,451,821
6,465,518
6,465,686
6,495,606
6,525,051
6,545,170
6,552,052
6,576,780
6,579,883
6,586,471
6,586,474
6,620,848
6,670,473
Target ValidationClick to Find Target Validation Information.    
Inhibitor (5-Imino-[1,4]thiazepan-3-yl)-methanol[14]
(5S,6R)-[Octahydro-quinolin-[15]
(5S,6S)-[Octahydro-quinolin-[15]
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin[16]
(S)-2-Amino-5-[17]
(S)-3-Propyl-[1,4]thiazepan-[14]
(S)-6-Amino-2-[14]
1,2,4-Triazole-Carboxamidine[16]
1- (2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea[18]
1- (2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea[18]
2,4-Diamino-6-Phenyl-5,6,7,8,-Tetrahydropteridine[19]
2-Amino-5- (N-nitro-guanidino)-pentanoic acid[17]
2-Aminothiazoline[16]
2-Methyl-2,4-Pentanediol[16]
2-Methyl-[1,4]thiazepan- (5E)-ylideneamine[14]
2-Propanol, Isopropanol[16]
3,4-Dimethyl-pyrrolidin- (2Z)-ylideneamine[20]
3-Bromo-1H-indazole-7-carbonitrile[21]
3-Bromo-7-Nitroindazole[16]
3-Ethyl-[1,4]thiazepan- (5E)-ylideneamine[14]
3-Methyl-[1,4]thiazepan- (5E)-ylideneamine[14]
3-Methyl-pyrrolidin- (2Z)-ylideneamine[20]
3-bromo-7-nitro-1H-indazole[21]
4,5-Dimethyl-pyrrolidin- (2Z)-ylideneamine[20]
4-Ethyl-5,6-dihydro-1H-pyridin- (2Z)-ylideneamine[22]
4-Ethyl-5-methyl-pyrrolidin- (2Z)-ylideneamine[20]
4-Ethyl-pyrrolidin- (2Z)-ylideneamine[20]
4-Methyl-3,6-dihydro-1H-pyridin- (2Z)-ylideneamine[22]
4-Methyl-5,6-dihydro-1H-pyridin- (2Z)-ylideneamine[22]
4-Methyl-piperidin- (2E)-ylideneamine[15]
4-Methyl-pyrrolidin- (2Z)-ylideneamine[20]
4-methyl-6-propylpyridin-2-amine[23]
4-methylpyridin-2-amine[23]
5,6-Cyclic-Tetrahydropteridine[24]
5-Ethyl-3-methyl-pyrrolidin- (2Z)-ylideneamine[20]
5-Ethyl-4-methyl-pyrrolidin- (2Z)-ylideneamine[20]
5-Methyl-pyrrolidin- (2Z)-ylideneamine[20]
5-Nitroindazole[16]
6- (2-Fluoropropyl)-4-methylpyridin-2-amine[25]
6- (3-Fluoropropyl)-4-methylpyridin-2-amine[25]
6-Nitroindazole[16]
6-isobutyl-4-methylpyridin-2-amine[25]
6s-5,6,7,8-Tetrahydrobiopterin[16]
7- (2-Nitro-ethyl)-azepan-[26]
7-Methyl-[1,4]thiazepan- (5E)-ylideneamine[14]
7-Nitroindazole[16]
7-Nitroindazole-2-Carboxamidine[19]
AP-Cav[11]
Acetate Ion[16]
Azepan- (2Z)-ylideneamine[26]
Cacodylate Ion[16]
Ethylisothiourea[16]
Heme[19]
Hexahydro-cyclopenta[c]pyrrol- (1Z)-ylideneamine[20]
Hydroxydimethylarsine Oxide[16]
L-2-Amino-4- (Guanidinooxy)Butyric Acid[16]
L-Homoarginine[16]
L-NAME[8][9][10]
L-NG-nitroarginine methyl ester[5]
L-NIO[27]
L-NMMA[1][2][3]
L-Nw-nitroarginine[28]
N,N-dimethylarginine[29]
N- (3-[19]
N- (5-Amino-6-oxo-heptyl)-acetamidine[20]
N- (Chlorophenyl)-N'-Hydroxyguanidine[19]
N-Omega-Hydroxy-L-Arginine[16]
N-omega-allyl-L-arginine[27]
N-omega-propargyl-L-arginine[27]
N1,N14-Bis ([16]
N5- (1-iminobut-3-enyl)-L-ornithine[27]
N5- (1-iminobutyl)-L-ornithine[27]
N5- (1-iminopropyl)-L-ornithine[27]
N5-Iminoethyl-L-Ornithine[24]
Nitroarginine[30]
Piperidin- (2E)-ylideneamine[15]
Pyrrolidin- (2Z)-ylideneamine[20]
S- (Dimethylarsenic)Cysteine[16]
S-Ethyl-N-Phenyl-Isothiourea[19]
S-Isopropyl-Isothiourea[16]
Se-Ethyl-Isoselenourea[16]
THIOCITRULLINE[31]
Thiazolidin- (2E)-ylideneamine[20]
[1,3]Oxazinan- (2E)-ylideneamine[17]
[1,3]Thiazinan- (2E)-ylideneamine[17]
[1,4]Oxazepan- (3E)-ylideneamine[14]
[1,4]Thiazepan- (3E)-ylideneamine[14]
[1,4]Thiazepan- (5E)-ylideneamine[14]
l-NIL[32]
StimulatorACCLAIM[6]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Gender is related to alterations of renal endothelial function in type 2 diabetes. Nephrol Dial Transplant. 2009 Jun 30. [Epub ahead of print] To Reference
Ref 2Gonadal 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. 2009 Jun 28. [Epub ahead of print] To Reference
Ref 3Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs. Intensive Care Med. 2009 Jun 24. [Epub ahead of print] To Reference
Ref 4Adenoviral gene transfer of eNOS: high-level expression in ex vivo expanded marrow stromal cells. Am J Physiol Cell Physiol. 2003 Nov;285(5):C1322-9. Epub 2003 Jul 23. To Reference
Ref 5COX-2 and iNOS, good targets for chemoprevention of colon cancer. Biofactors. 2000;12(1-4):129-33. To Reference
Ref 6CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008. To Reference
Ref 7Comparative study of the spatial relationship between nicotinamide adenine dinucleotide phosphate-diaphorase activity, serotonin immunoreactivity, and GYIRFamide immunoreactivity and the musculature of the adult liver fluke, Fasciola hepatica (Digenea, fasciolidae). J Comp Neurol. 2001 Jan 1;429(1):71-9. To Reference
Ref 8Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection. Vascul Pharmacol. 2009 Jul 5. [Epub ahead of print] To Reference
Ref 9Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contractility. Acta Physiol (Oxf). 2009 Jul 6. [Epub ahead of print] To Reference
Ref 10L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway. Mediators Inflamm. 2000;9(1):25-30. To Reference
Ref 11Endothelial nitric oxide synthase: the Cinderella of inflammation? Trends Pharmacol Sci. 2003 Feb;24(2):91-5. To Reference
Ref 12Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase. Psychopharmacology (Berl). 2001 May;155(3):299-309. To Reference
Ref 13Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise. Surg Infect (Larchmt). 2001 Summer;2(2):93-100; discussion 100-1. To Reference
Ref 14Bioorg 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. To Reference
Ref 15Bioorg 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. To Reference
Ref 16Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 17J Med Chem. 1996 Feb 2;39(3):669-72.2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. To Reference
Ref 18Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4. Epub 2007 Feb 8.Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. To Reference
Ref 19Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 20Bioorg 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. To Reference
Ref 21Bioorg 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. To Reference
Ref 22Bioorg 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. To Reference
Ref 23Nat Chem Biol. 2008 Nov;4(11):700-7. Epub 2008 Oct 12.Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. To Reference
Ref 24Nucleic Acids Res. 2011 January; 39(Database issue): D1035¨CD1041. DrugBank 3.0: a comprehensive resource for ¡®Omics¡¯ research on drugs To Reference
Ref 25J 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. To Reference
Ref 26Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. To Reference
Ref 27Bioorg 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. To Reference
Ref 28J 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. To Reference
Ref 29van Guldener C, Nanayakkara PW, Stehouwer CD: Review: Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med. 2007 Oct 15;. To Reference
Ref 30Raman CS, Li H, Martasek P, Southan G, Masters BS, Poulos TL: Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry. 2001 Nov 13;40(45):13448-55. To Reference
Ref 31Bioorg 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. To Reference
Ref 32Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43. Epub 2007 Oct 25.Discovery of a series of aminopiperidines as novel iNOS inhibitors. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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