Target Information
Target General Information | Top | |||||
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Target ID |
T78356
(Former ID: TTDC00086)
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Target Name |
Thromboxane-A synthase (TBXAS1)
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Synonyms |
Thromboxane A2 synthase; TXS; TXA synthase; Cytochrome P450 5A1; CYP5A1; CYP5
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Gene Name |
TBXAS1
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Angina pectoris [ICD-11: BA40] | |||||
Function |
endoplasmic reticulum membrane, 12-hydroxyheptadecatrienoic acid synthase activity, thromboxane-A synthase activity, cyclooxygenase pathway, icosanoid metabolic process.
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BioChemical Class |
Intramolecular oxidoreductase
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UniProt ID | ||||||
EC Number |
EC 5.3.99.5
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Sequence |
MEALGFLKLEVNGPMVTVALSVALLALLKWYSTSAFSRLEKLGLRHPKPSPFIGNLTFFR
QGFWESQMELRKLYGPLCGYYLGRRMFIVISEPDMIKQVLVENFSNFTNRMASGLEFKSV ADSVLFLRDKRWEEVRGALMSAFSPEKLNEMVPLISQACDLLLAHLKRYAESGDAFDIQR CYCNYTTDVVASVAFGTPVDSWQAPEDPFVKHCKRFFEFCIPRPILVLLLSFPSIMVPLA RILPNKNRDELNGFFNKLIRNVIALRDQQAAEERRRDFLQMVLDARHSASPMGVQDFDIV RDVFSSTGCKPNPSRQHQPSPMARPLTVDEIVGQAFIFLIAGYEIITNTLSFATYLLATN PDCQEKLLREVDVFKEKHMAPEFCSLEEGLPYLDMVIAETLRMYPPAFRFTREAAQDCEV LGQRIPAGAVLEMAVGALHHDPEHWPSPETFNPERFTAEARQQHRPFTYLPFGAGPRSCL GVRLGLLEVKLTLLHVLHKFRFQACPETQVPLQLESKSALGPKNGVYIKIVSR Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | NM-702 | Drug Info | Phase 3 | Angina pectoris | [2] | |
2 | E-6700 | Drug Info | Phase 2 | Asthma | [3] | |
3 | EV-077 | Drug Info | Phase 2 | Type-2 diabetes | [4] | |
4 | FK-070 | Drug Info | Phase 2 | Angina pectoris | [5] | |
5 | G-619 | Drug Info | Phase 1 | Thrombosis | [6] | |
6 | NV-52 | Drug Info | Phase 1 | Inflammatory bowel disease | [7] | |
Discontinued Drug(s) | [+] 5 Discontinued Drugs | + | ||||
1 | Satigrel | Drug Info | Discontinued in Preregistration | Thrombosis | [8] | |
2 | Imitrodast | Drug Info | Discontinued in Phase 2 | Asthma | [9] | |
3 | MILACAINIDE TARTRATE | Drug Info | Discontinued in Phase 2 | Cardiac arrhythmias | [10] | |
4 | Rolafagrel | Drug Info | Discontinued in Phase 2 | Nephritis | [11] | |
5 | CGS-13080 | Drug Info | Terminated | Asthma | [14] | |
Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
1 | ONO-1301 | Drug Info | Preclinical | Angina pectoris | [12], [13] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Inhibitor | [+] 15 Inhibitor drugs | + | ||||
1 | PYRIDINE | Drug Info | [1] | |||
2 | NM-702 | Drug Info | [15] | |||
3 | NV-52 | Drug Info | [17], [18] | |||
4 | Imitrodast | Drug Info | [20] | |||
5 | Rolafagrel | Drug Info | [22] | |||
6 | CGS-13080 | Drug Info | [24] | |||
7 | Dazoxiben | Drug Info | [25] | |||
8 | 2-(10-Imidazol-1-yl-decyl)-isoindole-1,3-dione | Drug Info | [26] | |||
9 | 2-(6-Imidazol-1-yl-hexyl)-isoindole-1,3-dione | Drug Info | [26] | |||
10 | 2-(8-Imidazol-1-yl-octyl)-isoindole-1,3-dione | Drug Info | [26] | |||
11 | 4-Methyl-pyridine | Drug Info | [1] | |||
12 | 5-(2-Imidazol-1-yl-ethyl)-7,8-dihydro-quinoline | Drug Info | [27] | |||
13 | 5-Imidazol-1-yl-5,6,7,8-tetrahydro-quinoline | Drug Info | [27] | |||
14 | 6-Imidazol-1-yl-isoquinoline | Drug Info | [27] | |||
15 | ONO-1581 | Drug Info | [29] | |||
Modulator | [+] 6 Modulator drugs | + | ||||
1 | E-6700 | Drug Info | [3] | |||
2 | EV-077 | Drug Info | [16] | |||
3 | FK-070 | Drug Info | [5] | |||
4 | G-619 | Drug Info | [6] | |||
5 | Satigrel | Drug Info | [19] | |||
6 | CV-6504.HCL | Drug Info | [28] | |||
Antagonist | [+] 1 Antagonist drugs | + | ||||
1 | MILACAINIDE TARTRATE | Drug Info | [21] | |||
Agonist | [+] 1 Agonist drugs | + | ||||
1 | ONO-1301 | Drug Info | [23] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Arachidonic acid metabolism | hsa00590 | Affiliated Target |
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Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
Platelet activation | hsa04611 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.72E-06 |
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Closeness centrality | 1.91E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
Neighborhood connectivity | 9.50E+00 | Topological coefficient | 8.50E-01 | Eccentricity | 13 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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BioCyc | [+] 1 BioCyc Pathways | + | ||||
1 | C20 prostanoid biosynthesis | |||||
KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
1 | Arachidonic acid metabolism | |||||
2 | Metabolic pathways | |||||
3 | Platelet activation | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Arachidonic Acid Metabolism | |||||
WikiPathways | [+] 4 WikiPathways | + | ||||
1 | Prostaglandin Synthesis and Regulation | |||||
2 | Arachidonic acid metabolism | |||||
3 | Phase 1 - Functionalization of compounds | |||||
4 | Eicosanoid Synthesis |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives. J Med Chem. 1981 Oct;24(10):1149-55. | |||||
REF 2 | Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication. Trials. 2011; 12: 134. | |||||
REF 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. | |||||
REF 4 | ClinicalTrials.gov (NCT01551381) Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of EV-077 in Type 2 Diabetic Subjects. U.S. National Institutes of Health. | |||||
REF 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. | |||||
REF 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. | |||||
REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017139) | |||||
REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000441) | |||||
REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000225) | |||||
REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001597) | |||||
REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001438) | |||||
REF 12 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1964). | |||||
REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005013) | |||||
REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000262) | |||||
REF 15 | 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. | |||||
REF 16 | Company report (Pharmaceuticalintelligence) | |||||
REF 17 | Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers. Drugs R D. 2008;9(3):159-66. | |||||
REF 18 | Nv-52: a novel thromboxane synthase inhibitor for the treatment of inflammatory bowel disease. Expert Opin Investig Drugs. 2007 Aug;16(8):1255-66. | |||||
REF 19 | 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. | |||||
REF 20 | RS-5186, a novel thromboxane synthetase inhibitor with a potent and extended duration of action. Thromb Res. 1988 Sep 1;51(5):507-20. | |||||
REF 21 | 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. | |||||
REF 22 | 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. | |||||
REF 23 | 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. | |||||
REF 24 | Imidazo[1,5-a]pyridines: a new class of thromboxane A2 synthetase inhibitors. J Med Chem. 1985 Feb;28(2):164-70. | |||||
REF 25 | Metabolic protection of the reperfused canine endocardium by the thromboxane synthetase inhibitor, dazoxiben. Prostaglandins Leukot Essent Fatty Acids. 1988 Jul;33(1):13-22. | |||||
REF 26 | 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. | |||||
REF 27 | 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. | |||||
REF 28 | Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats. Kidney Int. 1991 May;39(5):920-9. | |||||
REF 29 | Pharmacological evaluation of combined PGI2 agonists/thromboxane synthase inhibitors, Bioorg. Med. Chem. Lett. 5(10):1087-1090 (1995). |
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