Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTKNWZ4)

• DTT Name: Thromboxane-A synthase (TBXAS1)
• Synonyms: Thromboxane A2 synthase; TXS; TXA synthase; Cytochrome P450 5A1; CYP5A1; CYP5
• Gene Name: TBXAS1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Intramolecular oxidoreductase
• UniProt ID: THAS_HUMAN
• TTD ID: T78356
• EC Number: EC 5.3.99.5
• Sequence:
  MEALGFLKLEVNGPMVTVALSVALLALLKWYSTSAFSRLEKLGLRHPKPSPFIGNLTFFR
  QGFWESQMELRKLYGPLCGYYLGRRMFIVISEPDMIKQVLVENFSNFTNRMASGLEFKSV
  ADSVLFLRDKRWEEVRGALMSAFSPEKLNEMVPLISQACDLLLAHLKRYAESGDAFDIQR
  CYCNYTTDVVASVAFGTPVDSWQAPEDPFVKHCKRFFEFCIPRPILVLLLSFPSIMVPLA
  RILPNKNRDELNGFFNKLIRNVIALRDQQAAEERRRDFLQMVLDARHSASPMGVQDFDIV
  RDVFSSTGCKPNPSRQHQPSPMARPLTVDEIVGQAFIFLIAGYEIITNTLSFATYLLATN
  PDCQEKLLREVDVFKEKHMAPEFCSLEEGLPYLDMVIAETLRMYPPAFRFTREAAQDCEV
  LGQRIPAGAVLEMAVGALHHDPEHWPSPETFNPERFTAEARQQHRPFTYLPFGAGPRSCL
  GVRLGLLEVKLTLLHVLHKFRFQACPETQVPLQLESKSALGPKNGVYIKIVSR
• Function: endoplasmic reticulum membrane, 12-hydroxyheptadecatrienoic acid synthase activity, thromboxane-A synthase activity, cyclooxygenase pathway, icosanoid metabolic process.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Platelet activation (hsa04611)
• Reactome Pathway:
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Defective TBXAS1 causes GHDD (R-HSA-5579032)
  Eicosanoids (R-HSA-211979)
• BioCyc Pathway: MetaCyc:HS00728-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PYRIDINE	DMF8CJ9	N. A.	N. A.	Phase 4	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NM-702	DMDJLY9	Angina pectoris	BA40	Phase 3	[2]
E-6700	DMUWJI4	Asthma	CA23	Phase 2	[3]
EV-077	DM1FCDH	Type-2 diabetes	5A11	Phase 2	[4]
FK-070	DMJSD5W	Angina pectoris	BA40	Phase 2	[5]
G-619	DM3H6YC	Thrombosis	DB61-GB90	Phase 1	[6]
NV-52	DM0UOA9	Inflammatory bowel disease	DD72	Phase 1	[7]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Satigrel	DM4LSJ2	Thrombosis	DB61-GB90	Discontinued in Preregistration	[8]
Imitrodast	DMQ2ULV	Asthma	CA23	Discontinued in Phase 2	[9]
MILACAINIDE TARTRATE	DMJLNUD	Cardiac arrhythmias	BC9Z	Discontinued in Phase 2	[10]
Rolafagrel	DM8Q7XV	Nephritis	GB40	Discontinued in Phase 2	[11]
CGS-13080	DMUPKYO	Asthma	CA23	Terminated	[13]
Dazoxiben	DMJUW8H	N. A.	N. A.	Terminated	[14]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ONO-1301	DMMBIHO	Angina pectoris	BA40	Preclinical	[12]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(10-Imidazol-1-yl-decyl)-isoindole-1,3-dione	DMVXN01	Discovery agent	N.A.	Investigative	[15]
2-(6-Imidazol-1-yl-hexyl)-isoindole-1,3-dione	DMKI6GQ	Discovery agent	N.A.	Investigative	[15]
2-(8-Imidazol-1-yl-octyl)-isoindole-1,3-dione	DMLQ9WD	Discovery agent	N.A.	Investigative	[15]
4-Methyl-pyridine	DME6UOM	Discovery agent	N.A.	Investigative	[1]
5-(2-Imidazol-1-yl-ethyl)-7,8-dihydro-quinoline	DMCP5U8	Discovery agent	N.A.	Investigative	[16]
5-Imidazol-1-yl-5,6,7,8-tetrahydro-quinoline	DMVSBHU	Discovery agent	N.A.	Investigative	[16]
6-Imidazol-1-yl-isoquinoline	DMQXL1Y	Discovery agent	N.A.	Investigative	[16]
CV-6504.HCL	DMO9WZN	Discovery agent	N.A.	Investigative	[17]
ONO-1581	DMSXT0H	Discovery agent	N.A.	Investigative	[18]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	6.56E-01	0.02	0.08
Asthma	CA23	Nasal and bronchial airway	1.71E-03	0.08	0.24

References

• [1] Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives. J Med Chem. 1981 Oct;24(10):1149-55.
• [2] The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease. J Am Coll Cardiol. 2006 Dec 19;48(12):2539-45.
• [3] Structure-activity relationships of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)-alkyl]-2-propenoic acid derivatives that inhibit both 5-lipoxygenase and thromboxane A2 synthetase. J Med Chem. 1996 Aug 2;39(16):3148-57.
• [4] Company report (Pharmaceuticalintelligence)
• [5] Pharmacokinetic and pharmacodynamic properties of FK070 (KDI-792), a novel thromboxane receptor antagonist/thromboxane synthetase inhibitor, after single and multiple oral administrations to healthy volunteers. J Pharm Pharmacol. 1996 Apr;48(4):380-5.
• [6] G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, inhibits tumor necrosis factor-alpha biosynthesis. Eur J Pharmacol. 1995 Nov 3;286(1):31-9.
• [7] Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers. Drugs R D. 2008;9(3):159-66.
• [8] Mechanisms of satigrel (E5510), a new anti-platelet drug, in inhibiting human platelet aggregation. Selectivity and potency against prostaglandin H synthases isozyme activities and phosphodiesterase isoform activities. Biol Pharm Bull. 1996 Jun;19(6):828-33.
• [9] RS-5186, a novel thromboxane synthetase inhibitor with a potent and extended duration of action. Thromb Res. 1988 Sep 1;51(5):507-20.
• [10] Effects of the new class I antiarrhythmic agent Ro 22-9194, (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate, on ischemia- and reperfusion-induced arrhythmias in dogs: involvement of thromboxane A2 synthase inhibitory activity. J Pharmacol Exp Ther. 1996 Nov;279(2):877-83.
• [11] Inhibition by FCE 22178 of platelet and glomerular thromboxane synthase in animal and human kidney disease. Adv Prostaglandin Thromboxane Leukot Res. 1991;21B:707-10.
• [12] A synthetic prostacyclin agonist with thromboxane synthase inhibitory activity, ONO-1301, protects myocardium from ischemia/reperfusion injury. Eur J Pharmacol. 2012 Jan 15;674(2-3):352-8.
• [13] Imidazo[1,5-a]pyridines: a new class of thromboxane A2 synthetase inhibitors. J Med Chem. 1985 Feb;28(2):164-70.
• [14] Metabolic protection of the reperfused canine endocardium by the thromboxane synthetase inhibitor, dazoxiben. Prostaglandins Leukot Essent Fatty Acids. 1988 Jul;33(1):13-22.
• [15] Thromboxane synthetase inhibitors and antihypertensive agents. 2. N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones and N-[(1H-1,2,4-triazol-... J Med Chem. 1986 May;29(5):816-9.
• [16] 1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthas... J Med Chem. 2000 May 4;43(9):1841-51.
• [17] Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats. Kidney Int. 1991 May;39(5):920-9.
• [18] Pharmacological evaluation of combined PGI2 agonists/thromboxane synthase inhibitors, Bioorg. Med. Chem. Lett. 5(10):1087-1090 (1995).