Target Validation Information
TTD ID T06046
Target Name Nitric-oxide synthase endothelial (NOS3)
Type of Target
Clinical trial
Drug Potency against Target Drug Info IC50 = 3000 nM [14]
L-NAME Drug Info IC50 = 1000 nM [16]
Drug Info Ki = 750 nM [12]
(5-Imino-[1,4]thiazepan-3-yl)-methanol Drug Info IC50 = 6000 nM [4]
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine Drug Info IC50 = 5500 nM [5]
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine Drug Info IC50 = 12500 nM [5]
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid Drug Info IC50 = 5900 nM [13]
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info IC50 = 1000 nM [4]
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid Drug Info IC50 = 7900 nM [4]
1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea Drug Info IC50 = 12000 nM [7]
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea Drug Info IC50 = 9200 nM [7]
2-amino-4-methylpyridine Drug Info IC50 = 320 nM [10]
2-Amino-5-(N-nitro-guanidino)-pentanoic acid Drug Info IC50 = 500 nM [13]
2-Aminothiazoline Drug Info IC50 = 1100 nM [3]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info IC50 = 4100 nM [4]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 8700 nM [3]
3-Bromo-1H-indazole-7-carbonitrile Drug Info IC50 = 13000 nM [9]
3-bromo-7-nitro-1H-indazole Drug Info IC50 = 2000 nM [9]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info IC50 = 1100 nM [4]
3-Methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 1800 nM [3]
3-Methyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info IC50 = 5000 nM [4]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 600 nM [3]
4-Ethyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine Drug Info IC50 = 1500 nM [2]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 6300 nM [3]
4-Ethyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 14500 nM [3]
4-Methyl-3,6-dihydro-1H-pyridin-(2Z)-ylideneamine Drug Info IC50 = 440 nM [2]
4-Methyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine Drug Info IC50 = 230 nM [2]
4-methyl-6-propylpyridin-2-amine Drug Info IC50 = 34 nM [10]
4-Methyl-piperidin-(2E)-ylideneamine Drug Info IC50 = 146 nM [5]
4-Methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 2600 nM [3]
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 5500 nM [3]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 520 nM [3]
5-Methyl-pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 1900 nM [3]
6-(2-Fluoropropyl)-4-methylpyridin-2-amine Drug Info IC50 = 1500 nM [11]
6-(3-Fluoropropyl)-4-methylpyridin-2-amine Drug Info IC50 = 1428 nM [11]
6-isobutyl-4-methylpyridin-2-amine Drug Info IC50 = 150 nM [11]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine Drug Info IC50 = 2770 nM [1]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine Drug Info IC50 = 5000 nM [4]
Azepan-(2Z)-ylideneamine Drug Info IC50 = 15250 nM [1]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine Drug Info IC50 = 4700 nM [3]
L-NIL Drug Info IC50 = 2500 nM [8]
N-(5-Amino-6-oxo-heptyl)-acetamidine Drug Info IC50 = 7900 nM [3]
Piperidin-(2E)-ylideneamine Drug Info IC50 = 630 nM [5]
Pyrrolidin-(2Z)-ylideneamine Drug Info IC50 = 4600 nM [3]
THIOCITRULLINE Drug Info IC50 = 400 nM [6]
[1,3]Oxazinan-(2E)-ylideneamine Drug Info IC50 = 8200 nM [13]
[1,3]Thiazinan-(2E)-ylideneamine Drug Info IC50 = 7100 nM [13]
[1,4]Oxazepan-(3E)-ylideneamine Drug Info IC50 = 450 nM [4]
[1,4]Thiazepan-(3E)-ylideneamine Drug Info IC50 = 10500 nM [4]
[1,4]Thiazepan-(5E)-ylideneamine Drug Info IC50 = 13400 nM [4]
Action against Disease Model Drug Info We evaluated the contribution of endogenous and exogenous nitric oxide (NO) in ischaemia reperfusion (IR) injury and histamine release in the isolated guinea pig heart. Perfusion of the hearts with two inhibitors of the nitric oxide synthase pathway, namely N(G)-monomethyl-L-arginine (L-NMMA, 10(-4) M) or nitroarginine methylester (L-NAME, 10(-5) M) significantly enhanced histamine and LDH release; these effects were attenuated by co-infusion with L-arginine (10(-4) M) but not D-arginine (10(-4) M), while L-arginine (10(-4) M) alone had no effect. Perfusion of the heart with sodi uM nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1), glyceryl trinitrate (GTN), all at 10(-5) M, reduced histamine release, LDH release, calci uM overload and MDA production induced by IR. [15]
References
REF 1 Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.
REF 2 Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropy... Bioorg Med Chem Lett. 2002 Sep 2;12(17):2291-4.
REF 3 Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase. Bioorg Med Chem Lett. 2004 Sep 6;14(17):4539-44.
REF 4 Synthesis of analogs of (1,4)-3- and 5-imino oxazepane, thiazepane, and diazepane as inhibitors of nitric oxide synthases. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5907-11.
REF 5 Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inh... Bioorg Med Chem Lett. 2005 Apr 15;15(8):1997-2001.
REF 6 Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2881-5.
REF 7 Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4.
REF 8 Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43.
REF 9 Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile. Bioorg Med Chem. 2008 Jun 1;16(11):5962-73.
REF 10 Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat Chem Biol. 2008 Nov;4(11):700-7.
REF 11 Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fl... J Med Chem. 2009 Apr 23;52(8):2443-53.
REF 12 Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives. J Med Chem. 2010 Nov 11;53(21):7804-24.
REF 13 2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. J Med Chem. 1996 Feb 2;39(3):669-72.
REF 14 2-Amino-4-methylpyridine as a potent inhibitor of inducible NO synthase activity in vitro and in vivo. Br J Pharmacol. 1996 Nov;119(6):1101-8.
REF 15 Cardioprotective activity of endogenous and exogenous nitric oxide on ischaemia reperfusion injury in isolated guinea pig hearts. Inflamm Res. 1999 Nov;48(11):561-8.
REF 16 A cell-based nitric oxide reporter assay useful for the identification and characterization of modulators of the nitric oxide/guanosine 3',5'-cycli... Anal Biochem. 2007 Apr 15;363(2):219-27.

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