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Drug-Target Interaction

Drug

show drug details
PubChem ID:5472
Structure:
Synonyms:
5-((2-Chlorophenyl)methyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine
5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
5-[(2-chlorophenyl)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine
53-32C
55142-85-3
AC-15204
AC1L1KFB
BB_SC-2114
BIDD:PXR0169
BPBio1_000191
BRD-K00603606-003-03-4
BRN 1216802
BSPBio_000173
C07140
C14H14ClNS
CAS-53885-35-1
CHEBI:9588
CHEMBL833
D08594
DB00208
EINECS 259-498-5
HMS2089I18
L001108
LS-152434
MLS001201825
NCGC00016872-01
NCGC00016872-02
NCGC00016872-03
NCGC00016872-04
NCGC00016872-05
NCGC00016872-06
NCGC00016872-07
NCGC00016872-09
NCGC00016872-10
NCGC00024361-04
PCR 5332
Prestwick0_000047
Prestwick1_000047
Prestwick2_000047
Prestwick3_000047
SMR000641861
SPBio_002094
STK589340
STOCK5S-54105
Thieno(3,2-c)pyridine, 4,5,6,7-tetrahydro-5-((2-chlorophenyl)methyl)-
Thieno(3,2-c)pyridine, 5-((2-chlorophenyl)methyl)-4,5,6,7-tetrahydro-
Thieno[3,2-c]pyridine, 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydro-
Ticlid
Ticlodix
Ticlodone
Ticlopidin-Puren (TN)
Ticlopidina
Ticlopidina [INN-Spanish]
Ticlopidine
Ticlopidine (INN)
Ticlopidine HCL
TICLOPIDINE HYDROCHLORIDE
Ticlopidine [INN:BAN]
Ticlopidinum
Ticlopidinum [INN-Latin]
UNII-OM90ZUW7M1
UNM-0000345023
ZINC19594599
ATC-Codes:
Side-Effects:
Side-EffectFrequency
headache0
pancytopenia0
pain0
gastrointestinal hemorrhage0
ecchymosis0
hepatic failure0
vomiting0
tinnitus0
diarrhea0
sepsis0
asthenia0
colitis0
hepatic necrosis0
anaphylaxis0
allergic reaction0
serum sickness0
eosinophilia0
allergic alveolitis0
hyponatremia0
peptic ulcer0
thrombocythemia0
arthrosis0
anorexia0
nausea0
dyspepsia0
nephrotic syndrome0
epistaxis0
flatulence0
purpura0
positive ana0
hematuria0
angioedema0
jaundice0
peripheral neuropathy0
erythema multiforme0
rash0
thrombocytopenia0
hepatitis0
hemorrhage0
exfoliative dermatitis0
myositis0
renal failure0
urticaria0
hemolytic anemia0
pruritus0
dizziness0
leukemia0
lupus0
stevens - johnson syndrome0
vasculitis0

Target

show target details
Uniprot ID:CP2CJ_HUMAN
Synonyms:
(R)-limonene 6-monooxygenase
(S)-limonene 6-monooxygenase
(S)-limonene 7-monooxygenase
CYPIIC17
CYPIIC19
Cytochrome P450 2C19
Mephenytoin 4-hydroxylase
P450-11A
P450-254C
EC-Numbers:1.14.13.48
1.14.13.49
1.14.13.80
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----
----
----
----
----
----
----
----
----

References:

009390115
012721102
10
10233213
Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism.. T Tateishi; T Kumai; M Watanabe; H Nakura; M Tanaka; S Kobayashi (1999) British journal of clinical pharmacology display abstract
AIMS: To examine the effect of ticlopidine administration on the activities CYP2C19 and CYP3 A in vivo using omeprazole as a model substrate. METHODS: A single dose of 40 mg omeprazole was administered orally with or without ticlopidine (300 mg daily for 6 days) to six Japanese extensive metabolisers with respect to CYP2C19. Blood samples were taken for the measurement of plasma concentrations of omeprazole, 5-hydroxyomeprazole and omeprazole sulphone. RESULTS: Ticlopidine administration increased omeprazole Cmax (1978+/-859/ 3442+/-569 (control phase/ticlopidine phase, nm )) and decreased the oral clearance of omeprazole (CL/F; 25.70+/-16. 17/10.76+/-1.16 (control phase/ticlopidine phase, l h-1 )) significantly. The 5-hydroxyomeprazole to omeprazole AUC ratio (0. 817+/-0.448/0.236+/-0.053 (control phase/ticlopidine phase)) and the 5-hydroxyomeprazole to omeprazole sulphone AUC ratio (1.114+/-0. 782/0.256+/-0.051 (control phase/ticlopidine phase)) were decreased significantly after ticlopidine administration. The decrease in omeprazole CL/F and the 5-hydroxyomeprazole to omeprazole AUC ratio correlated significantly with their respective absolute values when the drug was given alone. The decrease in CL/F following ticlopidine administration correlated with that in the 5-hydroxyomeprazole to omeprazole AUC ratio. CONCLUSIONS: These findings suggest that ticlopidine inhibited the in vivo activity of CYP2C19, but not, or to a lesser extent CYP3 A4, and that the magnitude of inhibition by ticlopidine is related to the in vivo activity of CYP2C19 before inhibition.
10497136
11372587
11580286
Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19.. N T Ha-Duong; S Dijols; A C Macherey; J A Goldstein; P M Dansette; D Mansuy (2001) Biochemistry display abstract
Experiments using recombinant yeast-expressed human liver cytochromes P450 confirmed previous literature data indicating that ticlopidine is an inhibitor of CYP 2C19. The present studies demonstrated that ticlopidine is selective for CYP 2C19 within the CYP 2C subfamily. UV-visible studies on the interaction of a series of ticlopidine derivatives with CYP 2C19 showed that ticlopidine binds to the CYP 2C19 active site with a K(s) value of 2.8 +/- 1 microM. Derivatives that do not involve either the o-chlorophenyl substituent, the free tertiary amine function, or the thiophene ring of ticlopidine did not lead to such spectral interactions and failed to inhibit CYP 2C19. Ticlopidine is oxidized by CYP 2C19 with formation of two major metabolites, the keto tautomer of 2-hydroxyticlopidine (1) and the dimers of ticlopidine S-oxide (TSOD) (V(max) = 13 +/- 2 and 0.4 +/- 0.1 min(-1)). During this oxidation, CYP 2C19 was inactivated; the rate of its inactivation was time and ticlopidine concentration dependent. This process meets the chemical and kinetic criteria generally accepted for mechanism-based enzyme inactivation. It occurs in parralel with CYP 2C19-catalyzed oxidation of ticlopidine, is inhibited by an alternative well-known substrate of CYP 2C19, omeprazole, and correlates with the covalent binding of ticlopidine metabolite(s) to proteins. Moreover, CYP 2C19 inactivation is not inhibited by the presence of 5 mM glutathione, suggesting that it is due to an alkylation occurring inside the CYP 2C19 active site. The effects of ticlopidine on CYP 2C19 are very analogous with those previously described for the inactivation of CYP 2C9 by tienilic acid. This suggests that a similar electrophilic intermediate, possibly a thiophene S-oxide, is involved in the inactivation of CYP 2C19 and CYP 2C9 by ticlopidine and tienilic acid, respectively. The kinetic parameters calculated for ticlopidine-dependent inactivation of CYP 2C19, i.e., t(1/2max) = 3.4 min, k(inact) = 3.2 10(-3) s(-1), K(I) = 87 microM, k(inact)/K(I) = 37 L.mol(-1).s(-1), and r (partition ratio) = 26 (in relation with formation of 1 + TSOD), classify ticlopidine as an efficient mechanism-based inhibitor although somewhat less efficient than tienilic acid for CYP 2C9. Importantly, ticlopidine is the first selective mechanism-based inhibitor of human liver CYP 2C19 and should be a new interesting tool for studying the topology of the active site of CYP 2C19.
11764927
14977868
In vitro sulfoxidation of thioether compounds by human cytochrome P450 and flavin-containing monooxygenase isoforms with particular reference to the CYP2C subfamily.. Khawja A Usmani; Edward D Karoly; Ernest Hodgson; Randy L Rose (2004) Drug metabolism and disposition: the biological fate of chemicals display abstract
Cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are major catalysts involved in the metabolism of xenobiotics. The sulfoxidation of the thioether pesticides, phorate, disulfoton, sulprofos, and methiocarb, was investigated. Using pooled human liver microsomes (HLMs), thioether compounds displayed similar affinities; however, phorate and disulfoton displayed higher intrinsic clearance rates than either sulprofos or methiocarb. The sulfoxidation of thioethers by HLMs was found to be predominantly P450-driven (85-90%) compared with FMO (10-15%). Among 16 cDNA-expressed human P450 isoforms and 3 human FMO isoforms examined, the following isoforms and their polymorphisms had the highest rates for sulfoxidation, as follows: phorate, CYP1A2, 3A4, 2B6, 2C9*1, 2C18, 2C19, 2D6*1, and FMO1; disulfoton, CYP1A2, 3A4, 2B6, 2C9*1, 2C9*2, 2C18, 2C19, 2D6*1, and FMO1; sulprofos, CYP1A1, 1A2, 3A4, 2C9*1, 2C9*2, 2C9*3, 2C18, 2C19, 2D6*1, and FMO1; methiocarb, CYP1A1, 1A2, 3A4, 2B6, 2C9*1, 2C19, 2D6*1, and FMO1. Among these isoforms, members of the CYP2C subfamily often had the highest affinities and clearance rates. Moreover, sulfaphenazole, a CYP2C9 competitive inhibitor, inhibited disulfoton sulfoxidation by CYP2C9 (IC50 0.84 microM) as well as in HLMs. Ticlopidine, a CYP2C19 mechanism-based inhibitor, inhibited disulfoton sulfoxidation by CYP2C19 (IC50 after coincubation, 43.5 microM; IC50 after preincubation, 4.3 microM) and also in HLMs. Our results indicate that current models of the substrate binding site of the CYP2C subfamily would not effectively predict thioether pesticide metabolism. Thus, the substrate specificity of CYP2Cs is more extensive than is currently believed, and some reevaluation of structure-activity relationships may be required.
9390115
Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19.. S R Donahue; D A Flockhart; D R Abernethy; J W Ko (1997) Clinical pharmacology and therapeutics display abstract
A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.