Target Information

Target General Infomation
Target ID
T16117
Former ID
TTDC00063
Target Name
Nitric-oxide synthase, brain
Gene Name
NOS1
Synonyms
BNOS; Constitutive NOS; N-NOS; NC-NOS; NNOS; NOS, type I; Neuronal NOS; NOS1
Target Type
Clinical Trial
Disease Headache [ICD9: 339, 784.0; ICD10: G43-G44, R51]
Function
Produces 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. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T16117
UniProt ID
P29475
EC Number
EC 1.14.13.39
Sequence
MEDHMFGVQQIQPNVISVRLFKRKVGGLGFLVKERVSKPPVIISDLIRGGAAEQSGLIQA
GDIILAVNGRPLVDLSYDSALEVLRGIASETHVVLILRGPEGFTTHLETTFTGDGTPKTI
RVTQPLGPPTKAVDLSHQPPAGKEQPLAVDGASGPGNGPQHAYDDGQEAGSLPHANGLAP
RPPGQDPAKKATRVSLQGRGENNELLKEIEPVLSLLTSGSRGVKGGAPAKAEMKDMGIQV
DRDLDGKSHKPLPLGVENDRVFNDLWGKGNVPVVLNNPYSEKEQPPTSGKQSPTKNGSPS
KCPRFLKVKNWETEVVLTDTLHLKSTLETGCTEYICMGSIMHPSQHARRPEDVRTKGQLF
PLAKEFIDQYYSSIKRFGSKAHMERLEEVNKEIDTTSTYQLKDTELIYGAKHAWRNASRC
VGRIQWSKLQVFDARDCTTAHGMFNYICNHVKYATNKGNLRSAITIFPQRTDGKHDFRVW
NSQLIRYAGYKQPDGSTLGDPANVQFTEICIQQGWKPPRGRFDVLPLLLQANGNDPELFQ
IPPELVLEVPIRHPKFEWFKDLGLKWYGLPAVSNMLLEIGGLEFSACPFSGWYMGTEIGV
RDYCDNSRYNILEEVAKKMNLDMRKTSSLWKDQALVEINIAVLYSFQSDKVTIVDHHSAT
ESFIKHMENEYRCRGGCPADWVWIVPPMSGSITPVFHQEMLNYRLTPSFEYQPDPWNTHV
WKGTNGTPTKRRAIGFKKLAEAVKFSAKLMGQAMAKRVKATILYATETGKSQAYAKTLCE
IFKHAFDAKVMSMEEYDIVHLEHETLVLVVTSTFGNGDPPENGEKFGCALMEMRHPNSVQ
EERKSYKVRFNSVSSYSDSQKSSGDGPDLRDNFESAGPLANVRFSVFGLGSRAYPHFCAF
GHAVDTLLEELGGERILKMREGDELCGQEEAFRTWAKKVFKAACDVFCVGDDVNIEKANN
SLISNDRSWKRNKFRLTFVAEAPELTQGLSNVHKKRVSAARLLSRQNLQSPKSSRSTIFV
RLHTNGSQELQYQPGDHLGVFPGNHEDLVNALIERLEDAPPVNQMVKVELLEERNTALGV
ISNWTDELRLPPCTIFQAFKYYLDITTPPTPLQLQQFASLATSEKEKQRLLVLSKGLQEY
EEWKWGKNPTIVEVLEEFPSIQMPATLLLTQLSLLQPRYYSISSSPDMYPDEVHLTVAIV
SYRTRDGEGPIHHGVCSSWLNRIQADELVPCFVRGAPSFHLPRNPQVPCILVGPGTGIAP
FRSFWQQRQFDIQHKGMNPCPMVLVFGCRQSKIDHIYREETLQAKNKGVFRELYTAYSRE
PDKPKKYVQDILQEQLAESVYRALKEQGGHIYVCGDVTMAADVLKAIQRIMTQQGKLSAE
DAGVFISRMRDDNRYHEDIFGVTLRTYEVTNRLRSESIAFIEESKKDTDEVFSS
Drugs and Mode of Action
Drug(s) NXN-462 Drug Info Phase 2 Headache [524159]
L-NIL Drug Info Terminated Discovery agent [546719]
Inhibitor ((E)-7-But-2-enyl)-azepan-(2Z)-ylideneamine Drug Info [526140]
(+/-)-2-Methyl-1-(1-phenylethyl)-1H-imidazole Drug Info [531201]
(4S,5R)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
(4S,5R)-4,5-Dimethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
(4S,5S)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
(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]
(R)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
(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-amino-benzothiazol-5-yl)-2-ethyl-isothiourea Drug Info [528695]
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea Drug Info [528695]
1-(Benzhydrylamino)ethaniminium bromide Drug Info [531201]
1-Benzyl-2-methyl-1H-imidazole Drug Info [531201]
1-[(3-Methoxybenzyl)amino]ethaniminium chloride Drug Info [531201]
2'-Monophosphoadenosine 5'-Diphosphoribose Drug Info [551393]
2-(2-Amino-ethyl)-7-imino-azepane Drug Info [526140]
2-amino-4,6-dimethylpyridine Drug Info [530216]
2-Amino-5-(N-nitro-guanidino)-pentanoic acid Drug Info [534097]
2-aminopyridine Drug Info [530216]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
3,4-Dihydro-1H-quinolin-(2E)-ylideneamine Drug Info [527502]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
3-(2-Amino-ethyl)-5-imino-[1,4]oxazepane Drug Info [526140]
3-(2-Nitro-ethyl)-[1,4]oxazepan-(5Z)-ylideneamine Drug Info [526140]
3-Bromo-1H-indazole-7-carbonitrile Drug Info [529494]
3-bromo-7-nitro-1H-indazole Drug Info [530315]
3-Bromo-7-Nitroindazole Drug Info [551393]
3-Butyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
3-Isobutyl-[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]
3-Propyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
4,5,6,7-tetrafluoro-3-methyl-1H-indazole Drug Info [530315]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-bromo-1H-indazole Drug Info [528763]
4-Butyl-thiazolidin-(2E)-ylideneamine Drug Info [527210]
4-chloro-1H-indazole Drug Info [528763]
4-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-Ethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
4-Ethyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-iodo-1H-indazole Drug Info [528763]
4-Isopropyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-Methyl-5-propyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-methyl-6-propylpyridin-2-amine Drug Info [529745]
4-Methyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
4-Methyl-piperidin-(2E)-ylideneamine Drug Info [527502]
4-Methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
4-methylpyridin-2-amine Drug Info [529745]
4-[(2-Methyl-1H-imidazol-1-yl)methyl]pyridine Drug Info [531201]
5-bromo-1H-indazole Drug Info [528763]
5-Bromomethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
5-chloro-1H-indazole Drug Info [528763]
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
5-Ethyl-4-propyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
5-Ethyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
5-iodo-1H-indazole Drug Info [528763]
5-Methyl-oxazolidin-(2Z)-ylideneamine Drug Info [526912]
5-Methyl-pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
5-N-Allyl-Arginine Drug Info [551393]
6-(2-Fluoropropyl)-4-methylpyridin-2-amine Drug Info [530039]
6-(3-Fluoropropyl)-4-methylpyridin-2-amine Drug Info [530039]
6-bromo-1H-indazole Drug Info [528763]
6-chloro-1H-indazole Drug Info [528763]
6-isobutyl-4-methylpyridin-2-amine Drug Info [530039]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine Drug Info [526140]
7-bromo-1H-indazole Drug Info [528763]
7-Butyl-azepan-(2Z)-ylideneamine Drug Info [526140]
7-chloro-1H-indazole Drug Info [528763]
7-Methoxy-1H-indazole Drug Info [526052]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info [527266]
7-nitro-1H-indazole Drug Info [530315]
Acetate Ion Drug Info [551393]
Alpha-D-Mannose Drug Info [551393]
AR-C102222 Drug Info [529745]
AR-C133057XX Drug Info [529745]
Azepan-(2Z)-ylideneamine Drug Info [526140]
Azocan-(2Z)-ylideneamine Drug Info [526140]
Azonan-(2Z)-ylideneamine Drug Info [534097]
EUSYNSTYELAMIDE B Drug Info [530193]
Eusynstyelamide C Drug Info [530193]
Flavin-Adenine Dinucleotide Drug Info [551393]
Formic Acid Drug Info [551393]
Heme Drug Info [551374]
Hexahydro-cyclopenta[b]pyrrol-(2Z)-ylideneamine Drug Info [527210]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine Drug Info [527210]
Hexahydro-pyrrolizin-(3E)-ylideneamine Drug Info [527210]
L-NIL Drug Info [529159]
L-NIO Drug Info [529811]
L-Nw-nitroarginine Drug Info [531224]
N*1*-(5-Methyl-2-nitro-phenyl)-butane-1,4-diamine Drug Info [534663]
N-(3-(aminomethyl)-benzyl)acetamidine Drug Info [531201]
N-(3-(Aminomethyl)Benzyl)Acetamidine Drug Info [551374]
N-(5-Amino-6-oxo-heptyl)-acetamidine Drug Info [527210]
N-Butyl-N'-Hydroxyguanidine Drug Info [551393]
N-Isopropyl-N'-Hydroxyguanidine Drug Info [551393]
N-omega-allyl-L-arginine Drug Info [529811]
N-Omega-Hydroxy-L-Arginine Drug Info [551393]
N-omega-propargyl-L-arginine Drug Info [529811]
N-Omega-Propyl-L-Arginine Drug Info [551393]
N5-(1-Imino-3-Butenyl)-L-Ornithine Drug Info [551393]
N5-(1-iminobut-3-enyl)-L-ornithine Drug Info [529811]
N5-(1-iminobutyl)-L-ornithine Drug Info [529811]
N5-(1-iminopent-3-enyl)-L-ornithine Drug Info [529811]
N5-(1-iminopropyl)-L-ornithine Drug Info [529811]
Nitroarginine Drug Info [551396]
NXN-462 Drug Info [524159]
Octahydro-isoindol-(1Z)-ylideneamine Drug Info [527210]
Piperidin-(2E)-ylideneamine Drug Info [527502]
Pyrrolidin-(2Z)-ylideneamine Drug Info [527210]
S-Ethyl-N-Phenyl-Isothiourea Drug Info [551374]
S-Ethyl-N-[4-(Trifluoromethyl)Phenyl]Isothiourea Drug Info [551374]
Tetrahydro-pyrimidin-2-ylideneamine Drug Info [534097]
Thiazolidin-(2E)-ylideneamine Drug Info [527210]
THIOCITRULLINE Drug Info [527563]
[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]Oxazepan-(5E)-ylideneamine Drug Info [527266]
[1,4]Thiazepan-(3E)-ylideneamine Drug Info [527266]
[1,4]Thiazepan-(5E)-ylideneamine Drug Info [527266]
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
Phagosome
Circadian entrainment
Long-term depression
Salivary secretion
Alzheimer&#039
s disease
Amyotrophic lateral sclerosis (ALS)
NetPath Pathway EGFR1 Signaling Pathway
PANTHER Pathway CCKR signaling map ST
PathWhiz Pathway Arginine and Proline Metabolism
Reactome ROS production in response to bacteria
Nitric oxide stimulates guanylate cyclase
WikiPathways Monoamine Transport
Myometrial Relaxation and Contraction Pathways
Amyotrophic lateral sclerosis (ALS)
Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis
Spinal Cord Injury
Alzheimers Disease
Effects of Nitric Oxide
Serotonin Transporter Activity
References
Ref 524159ClinicalTrials.gov (NCT01748877) Efficacy, Tolerability, and Safety of NXN-462 in Patients With Post-Herpetic Neuralgia. U.S. National Institutes of Health.
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 524159ClinicalTrials.gov (NCT01748877) Efficacy, Tolerability, and Safety of NXN-462 in Patients With Post-Herpetic Neuralgia. U.S. National Institutes of Health.
Ref 526052Bioorg Med Chem Lett. 2001 May 7;11(9):1153-6.Inhibition of neuronal nitric oxide synthase by 7-methoxyindazole and related substituted indazoles.
Ref 526140Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase.
Ref 526912Bioorg 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.
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 528763Bioorg 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.
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 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 530193J Nat Prod. 2009 Jun;72(6):1115-20.Eusynstyelamides A, B, and C, nNOS inhibitors, from the ascidian Eusynstyela latericius.
Ref 530216J 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.
Ref 530315Bioorg 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.
Ref 531201Bioorg 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.
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 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 534663J Med Chem. 1998 Jul 2;41(14):2636-42.Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
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 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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