Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTCM4B3)

• DTT Name: Nitric-oxide synthase endothelial (NOS3)
• Synonyms: Nitric oxide synthase, endothelial; NOSIII; NOS,type III; NOS type III; Endothelial nitric oxide synthase; Endothelial NOS; ENOS; EC-NOS; Constitutive NOS; CNOS
• Gene Name: NOS3
• DTT Type: Clinical trial target; [1]
• Related Disease: Myocardial infarction [ICD-11: BA41-BA43]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: NOS3_HUMAN
• TTD ID: T06046
• EC Number: EC 1.14.13.39
• Sequence:
  MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
  QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP
  EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN
  APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD
  FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDDPP
  ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST
  EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH
  HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW
  KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR
  LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS
  PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF
  CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA
  RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL
  VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP
  PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY
  EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL
  AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP
  FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE
  PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD
  EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT
  NSP
• Function: NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  HIF-1 signaling pathway (hsa04066)
  Sphingolipid signaling pathway (hsa04071)
  PI3K-Akt signaling pathway (hsa04151)
  VEGF signaling pathway (hsa04370)
  Platelet activation (hsa04611)
  Estrogen signaling pathway (hsa04915)
  Oxytocin signaling pathway (hsa04921)
• Reactome Pathway:
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  eNOS activation (R-HSA-203615)
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  ROS production in response to bacteria (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS09149-MON

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tilarginine acetate	DMZBGI8	Myocardial infarction	BA41-BA43	Phase 3	[1]
ACCLAIM	DM0FGDO	Angina pectoris	BA40	Phase 2	[2]
L-NAME	DM01SR6	Hypertension	BA00-BA04	Phase 2	[3], [4], [5]
MTR105	DMT0K4F	Hypotension	BA20-BA21	Phase 2	[6]
VAS-203	DMKU93J	Brain injury	NA07.Z	Phase 2	[7]
Autologous cell based gene therapy	DMQA1VT	Pulmonary hypertension	BB01	Phase 1	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-NIL	DM6Y49D	N. A.	N. A.	Terminated	[9]

81 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5-Imino-[1,4]thiazepan-3-yl)-methanol	DMBKZDJ	Discovery agent	N.A.	Investigative	[10]
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine	DMT9CXD	Discovery agent	N.A.	Investigative	[11]
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine	DMP4UC1	Discovery agent	N.A.	Investigative	[11]
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin	DMOD9R7	Discovery agent	N.A.	Investigative	[12]
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid	DMZSWDM	Discovery agent	N.A.	Investigative	[13]
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine	DMIG9H3	Discovery agent	N.A.	Investigative	[10]
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid	DMG58HM	Discovery agent	N.A.	Investigative	[10]
1,2,4-Triazole-Carboxamidine	DMOXLHT	Discovery agent	N.A.	Investigative	[12]
1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea	DMAE8BF	Discovery agent	N.A.	Investigative	[14]
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea	DMCSHRL	Discovery agent	N.A.	Investigative	[14]
1400W	DMLZT64	Discovery agent	N.A.	Investigative	[15]
2,4-Diamino-6-Phenyl-5,6,7,8,-Tetrahydropteridine	DMQPKWM	Discovery agent	N.A.	Investigative	[15]
2-amino-4-methylpyridine	DM1OED2	Discovery agent	N.A.	Investigative	[16]
2-Amino-5-(N-nitro-guanidino)-pentanoic acid	DMDUZ2H	Discovery agent	N.A.	Investigative	[13]
2-Aminothiazoline	DM9YCAH	Discovery agent	N.A.	Investigative	[12], [17]
2-Methyl-2,4-Pentanediol	DMD45CU	Discovery agent	N.A.	Investigative	[12]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMX1IC4	Discovery agent	N.A.	Investigative	[10]
2-Propanol, Isopropanol	DML5O0H	Discovery agent	N.A.	Investigative	[12]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine	DMMO6QI	Discovery agent	N.A.	Investigative	[17]
3-Bromo-1H-indazole-7-carbonitrile	DMZGWL2	Discovery agent	N.A.	Investigative	[18]
3-bromo-7-nitro-1H-indazole	DMM7DHB	Discovery agent	N.A.	Investigative	[12], [18]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine	DMX2JKQ	Discovery agent	N.A.	Investigative	[10]
3-Methyl-pyrrolidin-(2Z)-ylideneamine	DMHVUF8	Discovery agent	N.A.	Investigative	[17]
3-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMCOH46	Discovery agent	N.A.	Investigative	[10]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine	DMB9CJM	Discovery agent	N.A.	Investigative	[17]
4-Ethyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine	DMTM1VD	Discovery agent	N.A.	Investigative	[19]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine	DMOAQ1E	Discovery agent	N.A.	Investigative	[17]
4-Ethyl-pyrrolidin-(2Z)-ylideneamine	DMYIWAH	Discovery agent	N.A.	Investigative	[17]
4-Methyl-3,6-dihydro-1H-pyridin-(2Z)-ylideneamine	DM5FWYG	Discovery agent	N.A.	Investigative	[19]
4-Methyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine	DMUP8NS	Discovery agent	N.A.	Investigative	[19]
4-methyl-6-propylpyridin-2-amine	DMY04D1	Discovery agent	N.A.	Investigative	[16]
4-Methyl-piperidin-(2E)-ylideneamine	DMNMXCE	Discovery agent	N.A.	Investigative	[11]
4-Methyl-pyrrolidin-(2Z)-ylideneamine	DM0YS36	Discovery agent	N.A.	Investigative	[17]
5,6-Cyclic-Tetrahydropteridine	DMDE7XJ	Discovery agent	N.A.	Investigative	[20]
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine	DMS9TFC	Discovery agent	N.A.	Investigative	[17]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine	DMQWOIG	Discovery agent	N.A.	Investigative	[17]
5-Methyl-pyrrolidin-(2Z)-ylideneamine	DM4QB3G	Discovery agent	N.A.	Investigative	[17]
5-Nitroindazole	DMH7SIX	Discovery agent	N.A.	Investigative	[12]
6-(2-Fluoropropyl)-4-methylpyridin-2-amine	DME1JLM	Discovery agent	N.A.	Investigative	[21]
6-(3-Fluoropropyl)-4-methylpyridin-2-amine	DMTJPZU	Discovery agent	N.A.	Investigative	[21]
6-isobutyl-4-methylpyridin-2-amine	DM2XB68	Discovery agent	N.A.	Investigative	[21]
6-Nitroindazole	DM2WZCX	Discovery agent	N.A.	Investigative	[12]
6s-5,6,7,8-Tetrahydrobiopterin	DMIA7ND	Discovery agent	N.A.	Investigative	[12]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine	DMK28IS	Discovery agent	N.A.	Investigative	[22]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine	DMUCJA6	Discovery agent	N.A.	Investigative	[10]
7-nitro-1H-indazole	DMW4XKQ	Discovery agent	N.A.	Investigative	[12]
7-Nitroindazole-2-Carboxamidine	DMGLWOM	Discovery agent	N.A.	Investigative	[15]
Acetate Ion	DMD08RH	Discovery agent	N.A.	Investigative	[12]
AP-Cav	DMT9Z5A	Discovery agent	N.A.	Investigative	[23]
Azepan-(2Z)-ylideneamine	DMZHV39	Discovery agent	N.A.	Investigative	[22]
Cacodylate Ion	DMK4XLD	Discovery agent	N.A.	Investigative	[12]
Ethylisothiourea	DMV9OCU	N. A.	N. A.	Investigative	[12]
Heme	DMGC287	Discovery agent	N.A.	Investigative	[15]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine	DMG0UVT	Discovery agent	N.A.	Investigative	[17]
Hydroxydimethylarsine Oxide	DMPS2B1	Discovery agent	N.A.	Investigative	[12]
L-2-Amino-4-(Guanidinooxy)Butyric Acid	DMWQCRD	Discovery agent	N.A.	Investigative	[12]
L-homoarginine	DML83XP	Discovery agent	N.A.	Investigative	[12]
L-NIO	DME9FAV	Discovery agent	N.A.	Investigative	[20], [24]
N,N-dimethylarginine	DM0Y8OW	Discovery agent	N.A.	Investigative	[25]
N-(5-Amino-6-oxo-heptyl)-acetamidine	DM47XR8	Discovery agent	N.A.	Investigative	[17]
N-(Chlorophenyl)-N'-Hydroxyguanidine	DMFGSLO	Discovery agent	N.A.	Investigative	[15]
N-omega-allyl-L-arginine	DM0BPCT	Discovery agent	N.A.	Investigative	[24]
N-Omega-Hydroxy-L-Arginine	DMOXQ3N	Discovery agent	N.A.	Investigative	[12]
N-omega-propargyl-L-arginine	DM9X3B7	Discovery agent	N.A.	Investigative	[24]
N1,N14-Bis((S-Methyl)Isothioureido)Tetradecane	DMVIGCJ	Discovery agent	N.A.	Investigative	[12]
N5-(1-iminobut-3-enyl)-L-ornithine	DMB62OI	Discovery agent	N.A.	Investigative	[24]
N5-(1-iminobutyl)-L-ornithine	DMT893N	Discovery agent	N.A.	Investigative	[24]
N5-(1-iminopropyl)-L-ornithine	DM05O7J	Discovery agent	N.A.	Investigative	[24]
Nitroarginine	DM7T80N	N. A.	N. A.	Investigative	[26]
Piperidin-(2E)-ylideneamine	DMN8OR2	Discovery agent	N.A.	Investigative	[11]
Pyrrolidin-(2Z)-ylideneamine	DMS4ZFU	Discovery agent	N.A.	Investigative	[17]
S-(Dimethylarsenic)Cysteine	DMSCHL0	Discovery agent	N.A.	Investigative	[12]
S-Ethyl-N-Phenyl-Isothiourea	DM6DT9Z	Discovery agent	N.A.	Investigative	[15]
S-Isopropyl-Isothiourea	DMZ30AM	Discovery agent	N.A.	Investigative	[12]
Se-Ethyl-Isoselenourea	DM9BJ27	Discovery agent	N.A.	Investigative	[12]
THIOCITRULLINE	DM7X8MH	Discovery agent	N.A.	Investigative	[27]
[1,3]Oxazinan-(2E)-ylideneamine	DMDX6W4	Discovery agent	N.A.	Investigative	[13]
[1,3]Thiazinan-(2E)-ylideneamine	DMOEIHC	Discovery agent	N.A.	Investigative	[13]
[1,4]Oxazepan-(3E)-ylideneamine	DMX58NK	Discovery agent	N.A.	Investigative	[10]
[1,4]Thiazepan-(3E)-ylideneamine	DMCBFJQ	Discovery agent	N.A.	Investigative	[10]
[1,4]Thiazepan-(5E)-ylideneamine	DMFQ0Z4	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	3.68E-01	-0.11	-0.85

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Nitric oxide synthase endothelial (NOS3) DME Info
• Gene Name: NOS3

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Solid tumour/cancer	2A00-2F9Z	Approved	[28]

References

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• [3] Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection. Vascul Pharmacol. 2009 Oct;51(4):253-61.
• [4] Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contracti... Acta Physiol (Oxf). 2009 Nov;197(3):253-64.
• [5] L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway. Mediators Inflamm. 2000;9(1):25-30.
• [6] Nitric oxide synthase inhibitor (MTR-105) during open-heart surgery. A pilot double-blind placebo-controlled study of hemodynamic effects and safety. Cardiology. 2008;111(3):181-7.
• [7] Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). J Neurotrauma. 2014 Oct 1;31(19):1599-606.
• [8] Feasibility of using autologous transplantation to evaluate hematopoietic stem cell-based gene therapy strategies in transgenic mouse models of human disease. Mol Ther. 2002 Sep;6(3):422-8.
• [9] Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43.
• [10] 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.
• [11] 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.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [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.
• [14] Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat Chem Biol. 2008 Nov;4(11):700-7.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [21] 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.
• [22] Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.
• [23] Endothelial nitric oxide synthase: the Cinderella of inflammation Trends Pharmacol Sci. 2003 Feb;24(2):91-5.
• [24] Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads. Bioorg Med Chem. 2008 Dec 15;16(24):10205-9.
• [25] Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med. 2007;45(12):1683-7.
• [26] Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry. 2001 Nov 13;40(45):13448-55.
• [27] 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.
• [28] The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004 Apr;18(6):664-75.