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Drug-Target Interaction

Drug

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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

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Uniprot ID:CP2C9_HUMAN
Synonyms:
(R)-limonene 6-monooxygenase
(S)-limonene 6-monooxygenase
(S)-limonene 7-monooxygenase
CYPIIC9
Cytochrome P450 2C9
P-450MP
P450 MP-4/MP-8
P450 PB-1
S-mephenytoin 4-hydroxylase
EC-Numbers:1.14.13.48
1.14.13.49
1.14.13.80
Organism:Homo sapiens
Human
PDB IDs:1OG2 1OG5 1R9O
Structure:
1R9O

Binding Affinities:

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

References:

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.