Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00063
Target NameNitric-oxide synthase, brain    
Type of TargetClinical trial target    
Drug Potency against TargetNXN-188Ki = 120 nM[1]
2-amino-4,6-dimethylpyridineIC50 = 100 nM[2]
6-isobutyl-4-methylpyridin-2-amineIC50 = 100 nM[3]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 1000 nM[4]
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acidIC50 = 10000 nM[5]
1-[(3-Methoxybenzyl)amino]ethaniminium chlorideIC50 = 10000 nM[6]
Azocan-(2Z)-ylideneamineIC50 = 10150 nM[7]
4-Isopropyl-pyrrolidin-(2Z)-ylideneamineIC50 = 10600 nM[8]
(4S,5R)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamineIC50 = 1200 nM[9]
3-Butyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 1200 nM[4]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamineIC50 = 130 nM[8]
4-Butyl-thiazolidin-(2E)-ylideneamineIC50 = 13200 nM[8]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 140 nM[8]
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothioureaIC50 = 1400 nM[10]
5-Methyl-oxazolidin-(2Z)-ylideneamineIC50 = 1400 nM[9]
ONO-1714IC50 = 15 nM[9]
4-Methyl-piperidin-(2E)-ylideneamineIC50 = 16 nM[11]
4-methylpyridin-2-amineIC50 = 160 nM[12]
[1,4]Oxazepan-(3E)-ylideneamineIC50 = 160 nM[4]
(4S,5R)-4,5-Dimethyl-oxazolidin-(2Z)-ylideneamineIC50 = 1600 nM[9]
Tetrahydro-pyrimidin-2-ylideneamineIC50 = 17000 nM[5]
5-Ethyl-4-propyl-pyrrolidin-(2Z)-ylideneamineIC50 = 17300 nM[8]
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acidIC50 = 17500 nM[4]
N-(5-Amino-6-oxo-heptyl)-acetamidineIC50 = 17500 nM[8]
3-Methyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 1800 nM[4]
5-Ethyl-oxazolidin-(2Z)-ylideneamineIC50 = 1800 nM[9]
Thiazolidin-(2E)-ylideneamineIC50 = 1800 nM[8]
3-Isobutyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 1900 nM[4]
4-methyl-6-propylpyridin-2-amineIC50 = 23 nM[12]
Piperidin-(2E)-ylideneamineIC50 = 240 nM[11]
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 2400 nM[8]
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amineIC50 = 246 nM[11]
(4S,5S)-4,5-Diethyl-oxazolidin-(2Z)-ylideneamineIC50 = 2500 nM[9]
3-Bromo-1H-indazole-7-carbonitrileIC50 = 2500 nM[13]
N*1*-(5-Methyl-2-nitro-phenyl)-butane-1,4-diamineIC50 = 2500 nM[14]
4-Ethyl-pyrrolidin-(2Z)-ylideneamineIC50 = 2600 nM[8]
(5-Imino-[1,4]thiazepan-3-yl)-methanolIC50 = 2700 nM[4]
3-Propyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 2800 nM[4]
[1,4]Thiazepan-(3E)-ylideneamineIC50 = 2800 nM[4]
4-Ethyl-oxazolidin-(2Z)-ylideneamineIC50 = 2800 nM[9]
1-(Benzhydrylamino)ethaniminium bromideIC50 = 300 nM[6]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamineIC50 = 310 nM[8]
5-Methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 3100 nM[8]
[1,3]Thiazinan-(2E)-ylideneamineIC50 = 3200 nM[5]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamineIC50 = 339 nM[7]
((E)-7-But-2-enyl)-azepan-(2Z)-ylideneamineIC50 = 3390 nM[7]
Azepan-(2Z)-ylideneamineIC50 = 3500 nM[7]
[1,3]Oxazinan-(2E)-ylideneamineIC50 = 3700 nM[5]
5-Bromomethyl-oxazolidin-(2Z)-ylideneamineIC50 = 400 nM[9]
EUSYNSTYELAMIDE BIC50 = 4300 nM[15]
[1,4]Thiazepan-(5E)-ylideneamineIC50 = 4300 nM[4]
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 440 nM[4]
1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothioureaIC50 = 4600 nM[10]
4-Methyl-5-propyl-pyrrolidin-(2Z)-ylideneamineIC50 = 4800 nM[8]
6-(2-Fluoropropyl)-4-methylpyridin-2-amineIC50 = 490 nM[3]
3,4-Dihydro-1H-quinolin-(2E)-ylideneamineIC50 = 4900 nM[11]
2-Amino-5-(N-nitro-guanidino)-pentanoic acidIC50 = 500 nM[5]
(+/-)-2-Methyl-1-(1-phenylethyl)-1H-imidazoleIC50 = 5000 nM[6]
4-[(2-Methyl-1H-imidazol-1-yl)methyl]pyridineIC50 = 5000 nM[6]
1-Benzyl-2-methyl-1H-imidazoleIC50 = 5000 nM[6]
6-(3-Fluoropropyl)-4-methylpyridin-2-amineIC50 = 514 nM[3]
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amineIC50 = 530 nM[11]
Eusynstyelamide CIC50 = 5800 nM[15]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 590 nM[4]
THIOCITRULLINEIC50 = 60 nM[16]
AR-C133057XXIC50 = 6000 nM[12]
l-NILIC50 = 6000 nM[17]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamineIC50 = 610 nM[8]
4-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 610 nM[8]
3-(2-Nitro-ethyl)-[1,4]oxazepan-(5Z)-ylideneamineIC50 = 6240 nM[7]
7-Methoxy-1H-indazoleIC50 = 6300 nM[18]
Octahydro-isoindol-(1Z)-ylideneamineIC50 = 660 nM[8]
Azonan-(2Z)-ylideneamineIC50 = 6800 nM[5]
(R)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 7100 nM[4]
N-(3-(aminomethyl)-benzyl)acetamidineIC50 = 7300 nM[6]
AR-C102222IC50 = 790 nM[12]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 80 nM[8]
4-Methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 800 nM[8]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamineIC50 = 830 nM[4]
3-(2-Amino-ethyl)-5-imino-[1,4]oxazepaneIC50 = 8390 nM[7]
7-Butyl-azepan-(2Z)-ylideneamineIC50 = 850 nM[7]
2-aminopyridineIC50 = 8700 nM[2]
[1,4]Oxazepan-(5E)-ylideneamineIC50 = 8700 nM[4]
3-Methyl-pyrrolidin-(2Z)-ylideneamineIC50 = 900 nM[8]
2-(2-Amino-ethyl)-7-imino-azepaneIC50 = 932 nM[7]
Hexahydro-pyrrolizin-(3E)-ylideneamineIC50 = 9600 nM[8]
Pyrrolidin-(2Z)-ylideneamineIC50 = 9600 nM[8]
4-Methyl-oxazolidin-(2Z)-ylideneamineIC50 = 9800 nM[9]
Hexahydro-cyclopenta[b]pyrrol-(2Z)-ylideneamineIC50 = 9900 nM[8]
L-Nw-nitroarginineKi = 4550 nM[19]
Action against Disease ModelGW274150GW274150 was effective in inhibiting LPS-induced plasma NO(x) levels in mice with an ED(50) of 3.2+/-0.7 mg kg(-1) after 14 h intraperitoneally (i.p.) and 3.8+/-1.5 mg kg(-1) after 14 h when administered orally. GW273629 showed shorter-lived effects on plasma NO(x) and an ED(50) of 9+/-2 mg kg(-1) after 2 h when administered i.p. 5 The effects of GW274150 and GW273629 in vivo were consistent with high selectivity for iNOS, as these inhibitors were of low potency against nNOS in the rat cerebell uM and did not cause significant effects on blood pressure in instr uMented mice.[20]
The Effect of Target Knockout, Knockdown or Genetic VariationsReduced tissue damage in experimental models of stroke and global cerebral ischaemia;Reduced neurotransmitter release;Altered airway responsiveness;Increased leukocyte adhesion;Increased stomach size (pyloric stenosis);Gastroparesis, abnormal IJP and NANC[21]
Ref 1Chapter 2 Advancements in the Development of Nitric Oxide Synthase Inhibitors. Annual Reports in Medicinal Chemistry. Volume 44, 2009, Pages 27-50 To Reference
Ref 2J 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 3J 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 4Bioorg 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 5J 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 6Bioorg 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 7Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. To Reference
Ref 8Bioorg 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 9Bioorg 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 10Bioorg 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 11Bioorg 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 12Nat 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 13Bioorg 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 14J Med Chem. 1998 Jul 2;41(14):2636-42.Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase. To Reference
Ref 15J Nat Prod. 2009 Jun;72(6):1115-20.Eusynstyelamides A, B, and C, nNOS inhibitors, from the ascidian Eusynstyela latericius. To Reference
Ref 16Bioorg 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 17Bioorg 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
Ref 18Bioorg 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 19J 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 20Br J Pharmacol. 2005 Jun;145(3):301-12.GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. To Reference
Ref 21Nat Rev Drug Discov. 2002 Dec;1(12):939-50.Blocking NO synthesis: how, where and why? To Reference



 

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Professor in Department of Pharmacy
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