Therapeutic Targets Database
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TTD Target ID: TTDC00063

Target Information
NameNitric-oxide synthase, brain    
Type of targetClinical trial target    
SynonymsBNOS    
Constitutive NOS    
N-NOS    
NC-NOS    
NNOS    
NOS, type I    
Neuronal NOS    
DiseaseHelminth infection
[ICD9: 001-139   ICD10: A00-B99]
[1]
Migraine and Cluster Headaches
[ICD9: 339.00, 339.01, 339.02, 346   ICD10: G43, G44.0]
[2]
Schizophrenia
[ICD9: 295   ICD10: F20]
[3][4]
Drug(s)NXN-188Phase IMigraine and Cluster Headaches[5]
BioChemical ClassOxidoreductases acting on paired donors    
EC NumberEC 1.14.13.39
PathwayAlzheimer's disease
Amyotrophic lateral sclerosis (ALS)
Arginine and proline metabolism
Calcium signaling pathway
Long-term depression
Metabolic pathways
Pathways in cancer
Small cell lung cancer
UniProt IDP29475
FunctionProduces nitric oxide (no) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, no displays many properties of a neurotransmitter.    
SequenceMEDHMFGVQQIQPNVISVRLFKRKVGGLGFLVKERVSKPPVIISDLIRGGAAEQSGLIQA GDIILAVNGRPLVDLSYDSALEVLRGIASETHVVLILRGPEGFTTHLETTFTGDGTPKTI RVTQPLGPPTKAVDLSHQPPAGKEQPLAVDGASGPGNGPQHAYDDGQEAGSLPHANGLAP RPPGQDPAKKATRVSLQGRGENNELLKEIEPVLSLLTSGSRGVKGGAPAKAEMKDMGIQV DRDLDGKSHKPLPLGVENDRVFNDLWGKGNVPVVLNNPYSEKEQPPTSGKQSPTKNGSPS KCPRFLKVKNWETEVVLTDTLHLKSTLETGCTEYICMGSIMHPSQHARRPEDVRTKGQLF PLAKEFIDQYYSSIKRFGSKAHMERLEEVNKEIDTTSTYQLKDTELIYGAKHAWRNASRC VGRIQWSKLQVFDARDCTTAHGMFNYICNHVKYATNKGNLRSAITIFPQRTDGKHDFRVW NSQLIRYAGYKQPDGSTLGDPANVQFTEICIQQGWKPPRGRFDVLPLLLQANGNDPELFQ IPPELVLEVPIRHPKFEWFKDLGLKWYGLPAVSNMLLEIGGLEFSACPFSGWYMGTEIGV RDYCDNSRYNILEEVAKKMNLDMRKTSSLWKDQALVEINIAVLYSFQSDKVTIVDHHSAT ESFIKHMENEYRCRGGCPADWVWIVPPMSGSITPVFHQEMLNYRLTPSFEYQPDPWNTHV WKGTNGTPTKRRAIGFKKLAEAVKFSAKLMGQAMAKRVKATILYATETGKSQAYAKTLCE IFKHAFDAKVMSMEEYDIVHLEHETLVLVVTSTFGNGDPPENGEKFGCALMEMRHPNSVQ EERKSYKVRFNSVSSYSDSQKSSGDGPDLRDNFESAGPLANVRFSVFGLGSRAYPHFCAF GHAVDTLLEELGGERILKMREGDELCGQEEAFRTWAKKVFKAACDVFCVGDDVNIEKANN SLISNDRSWKRNKFRLTFVAEAPELTQGLSNVHKKRVSAARLLSRQNLQSPKSSRSTIFV RLHTNGSQELQYQPGDHLGVFPGNHEDLVNALIERLEDAPPVNQMVKVELLEERNTALGV ISNWTDELRLPPCTIFQAFKYYLDITTPPTPLQLQQFASLATSEKEKQRLLVLSKGLQEY EEWKWGKNPTIVEVLEEFPSIQMPATLLLTQLSLLQPRYYSISSSPDMYPDEVHLTVAIV SYRTRDGEGPIHHGVCSSWLNRIQADELVPCFVRGAPSFHLPRNPQVPCILVGPGTGIAP FRSFWQQRQFDIQHKGMNPCPMVLVFGCRQSKIDHIYREETLQAKNKGVFRELYTAYSRE PDKPKKYVQDILQEQLAESVYRALKEQGGHIYVCGDVTMAADVLKAIQRIMTQQGKLSAE DAGVFISRMRDDNRYHEDIFGVTLRTYEVTNRLRSESIAFIEESKKDTDEVFSS
Related US Patent6,225,305
6,297,276
6,344,473
6,344,483
6,355,689
6,362,195
6,372,733
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6,403,830
6,410,542
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Target ValidationClick to Find Target Validation Information.    
Inhibitor ([6]
(+/-)-2-Methyl-1-[7]
(4S,5R)-4,5-Diethyl-oxazolidin-[8]
(4S,5R)-4,5-Dimethyl-oxazolidin-[8]
(4S,5S)-4,5-Diethyl-oxazolidin-[8]
(5-Imino-[1,4]thiazepan-3-yl)-methanol[9]
(5S,6R)-[Octahydro-quinolin-[10]
(5S,6S)-[Octahydro-quinolin-[10]
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin[11]
(R)-3-Propyl-[1,4]thiazepan-[9]
(S)-2-Amino-5-[12]
(S)-3-Propyl-[1,4]thiazepan-[9]
(S)-6-Amino-2-[9]
1- (2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea[13]
1- (2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea[13]
1- (Benzhydrylamino)ethaniminium bromide[7]
1-Benzyl-2-methyl-1H-imidazole[7]
1-[ (3-Methoxybenzyl)amino]ethaniminium chloride[7]
2'-Monophosphoadenosine 5'-Diphosphoribose[11]
2- (2-Amino-ethyl)-7-imino-azepane[6]
2-Amino-5- (N-nitro-guanidino)-pentanoic acid[12]
2-Methyl-[1,4]thiazepan- (5E)-ylideneamine[9]
2-amino-4,6-dimethylpyridine[14]
2-aminopyridine[14]
3,4-Dihydro-1H-quinolin- (2E)-ylideneamine[10]
3,4-Dimethyl-pyrrolidin- (2Z)-ylideneamine[15]
3- (2-Amino-ethyl)-5-imino-[1,4]oxazepane[6]
3- (2-Nitro-ethyl)-[1,4]oxazepan-[6]
3-Bromo-1H-indazole-7-carbonitrile[16]
3-Bromo-7-Nitroindazole[11]
3-Butyl-[1,4]thiazepan- (5E)-ylideneamine[9]
3-Ethyl-[1,4]thiazepan- (5E)-ylideneamine[9]
3-Isobutyl-[1,4]thiazepan- (5E)-ylideneamine[9]
3-Methyl-[1,4]thiazepan- (5E)-ylideneamine[9]
3-Methyl-pyrrolidin- (2Z)-ylideneamine[15]
3-Propyl-[1,4]thiazepan- (5E)-ylideneamine[9]
3-bromo-7-nitro-1H-indazole[17]
4,5,6,7-tetrafluoro-3-methyl-1H-indazole[17]
4,5-Dimethyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Butyl-thiazolidin- (2E)-ylideneamine[15]
4-Ethyl-3-methyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Ethyl-5-methyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Ethyl-oxazolidin- (2Z)-ylideneamine[8]
4-Ethyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Isopropyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Methyl-5-propyl-pyrrolidin- (2Z)-ylideneamine[15]
4-Methyl-oxazolidin- (2Z)-ylideneamine[8]
4-Methyl-piperidin- (2E)-ylideneamine[10]
4-Methyl-pyrrolidin- (2Z)-ylideneamine[15]
4-[ (2-Methyl-1H-imidazol-1-yl)methyl]pyridine[7]
4-bromo-1H-indazole[18]
4-chloro-1H-indazole[18]
4-iodo-1H-indazole[18]
4-methyl-6-propylpyridin-2-amine[19]
4-methylpyridin-2-amine[19]
5-Bromomethyl-oxazolidin- (2Z)-ylideneamine[8]
5-Ethyl-3-methyl-pyrrolidin- (2Z)-ylideneamine[15]
5-Ethyl-4-methyl-pyrrolidin- (2Z)-ylideneamine[15]
5-Ethyl-4-propyl-pyrrolidin- (2Z)-ylideneamine[15]
5-Ethyl-oxazolidin- (2Z)-ylideneamine[8]
5-Methyl-oxazolidin- (2Z)-ylideneamine[8]
5-Methyl-pyrrolidin- (2Z)-ylideneamine[15]
5-N-Allyl-Arginine[11]
5-bromo-1H-indazole[18]
5-chloro-1H-indazole[18]
5-iodo-1H-indazole[18]
6- (2-Fluoropropyl)-4-methylpyridin-2-amine[20]
6- (3-Fluoropropyl)-4-methylpyridin-2-amine[20]
6-bromo-1H-indazole[18]
6-chloro-1H-indazole[18]
6-isobutyl-4-methylpyridin-2-amine[20]
7- (2-Nitro-ethyl)-azepan-[6]
7-Butyl-azepan- (2Z)-ylideneamine[6]
7-Methoxy-1H-indazole[21]
7-Methyl-[1,4]thiazepan- (5E)-ylideneamine[9]
7-bromo-1H-indazole[18]
7-chloro-1H-indazole[18]
7-nitro-1H-indazole[17]
AR-C102222[19]
AR-C133057XX[19]
Acetate Ion[11]
Alpha-D-Mannose[11]
Azepan- (2Z)-ylideneamine[6]
Azocan- (2Z)-ylideneamine[6]
Azonan- (2Z)-ylideneamine[12]
EUSYNSTYELAMIDE B[22]
Eusynstyelamide C[22]
Flavin-Adenine Dinucleotide[11]
Formic Acid[11]
Heme[23]
Hexahydro-cyclopenta[b]pyrrol- (2Z)-ylideneamine[15]
Hexahydro-cyclopenta[c]pyrrol- (1Z)-ylideneamine[15]
Hexahydro-pyrrolizin- (3E)-ylideneamine[15]
L-NIO[24]
L-Nw-nitroarginine[25]
N*1*- (5-Methyl-2-nitro-phenyl)-butane-1,4-diamine[26]
N- (3-[23]
N- (3-[7]
N- (5-Amino-6-oxo-heptyl)-acetamidine[15]
N-Butyl-N'-Hydroxyguanidine[11]
N-Isopropyl-N'-Hydroxyguanidine[11]
N-Omega-Hydroxy-L-Arginine[11]
N-Omega-Propyl-L-Arginine[11]
N-omega-allyl-L-arginine[24]
N-omega-propargyl-L-arginine[24]
N5- (1-Imino-3-Butenyl)-L-Ornithine[11]
N5- (1-iminobut-3-enyl)-L-ornithine[24]
N5- (1-iminobutyl)-L-ornithine[24]
N5- (1-iminopent-3-enyl)-L-ornithine[24]
N5- (1-iminopropyl)-L-ornithine[24]
NXN-188[5]
Nitroarginine[27]
ONO-1714[8]
Octahydro-isoindol- (1Z)-ylideneamine[15]
Piperidin- (2E)-ylideneamine[10]
Pyrrolidin- (2Z)-ylideneamine[15]
Riboflavin Monophosphate[23]
S-Ethyl-N-Phenyl-Isothiourea[23]
S-Ethyl-N-[4- (Trifluoromethyl)Phenyl]Isothiourea[23]
THIOCITRULLINE[28]
Tetrahydro-pyrimidin-2-ylideneamine[12]
Thiazolidin- (2E)-ylideneamine[15]
[1,3]Oxazinan- (2E)-ylideneamine[12]
[1,3]Thiazinan- (2E)-ylideneamine[12]
[1,4]Oxazepan- (3E)-ylideneamine[9]
[1,4]Oxazepan- (5E)-ylideneamine[9]
[1,4]Thiazepan- (3E)-ylideneamine[9]
[1,4]Thiazepan- (5E)-ylideneamine[9]
l-NIL[29]
MultitargetNXN-188[5]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Comparative 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 2CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008. To Reference
Ref 3Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase. Psychopharmacology (Berl). 2001 May;155(3):299-309. To Reference
Ref 4News on NOS: neuronal nitric oxide synthase as a drug target. Neuroreport. 1994 Oct 3;5(15):1851-2. To Reference
Ref 5NeurAxon Announces Positive Phase 1 Trial Data on NXN-188 for Migraine. NeurAxon, Inc. 2007 To Reference
Ref 6Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. To Reference
Ref 7Bioorg Med Chem Lett. 2010 Nov 15;20(22):6495-9. Epub 2010 Sep 17.N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase. To Reference
Ref 8Bioorg Med Chem Lett. 2004 Jan 19;14(2):313-6.4,5-Disubstituted-1,3-oxazolidin-2-imine derivatives: a new class of orally bioavailable nitric oxide synthase inhibitor. To Reference
Ref 9Bioorg 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 10Bioorg 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 11Overington 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 12J 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 13Bioorg 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 14J Med Chem. 2009 Jul 23;52(14):4533-7.L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors. To Reference
Ref 15Bioorg 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 16Bioorg 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 17Bioorg Med Chem. 2009 Sep 1;17(17):6180-7. Epub 2009 Aug 6.Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation. To Reference
Ref 18Bioorg Med Chem Lett. 2007 Jun 1;17(11):3177-80. Epub 2007 Mar 14.4-substituted indazoles as new inhibitors of neuronal nitric oxide synthase. To Reference
Ref 19Nat 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 20J 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 21Bioorg Med Chem Lett. 2001 May 7;11(9):1153-6.Inhibition of neuronal nitric oxide synthase by 7-methoxyindazole and related substituted indazoles. To Reference
Ref 22J Nat Prod. 2009 Jun;72(6):1115-20.Eusynstyelamides A, B, and C, nNOS inhibitors, from the ascidian Eusynstyela latericius. To Reference
Ref 23Berman 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 24Bioorg 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 25J 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 26J Med Chem. 1998 Jul 2;41(14):2636-42.Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase. To Reference
Ref 27Raman 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 28Bioorg 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 29Bioorg 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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