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Drug-Target Interaction

Drug

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PubChem ID:5591
Structure:
Synonyms:
()-5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione
(+)-all-rac-5-(p-((6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy)benzyl)-2,4-thiazolidinedione
(+-)-all-rac-5-(p-((6-Hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy)benzyl)-2,4-thiazolidinedione
(+/-)-5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione
2,4-Thiazolidinedione, 5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-
2,4-Thiazolidinedione, 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]- (9CI)
5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl)-2,4-thiazolidinedione)
5-(4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl)thiazolidine
5-(4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl)thiazolidine-2,4-dione
5-[(4-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]oxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione
5-[[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione
5-[[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
5-{4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione
97322-87-7
BRN 4338399
C057693
C24H27NO5S
CCRIS 8969
CHEBI:9753
CI 991
CI-991
CS 045
CS-045
D00395
DB00197
GR 92132X
GR-92132X
HSCI1_000037
LS-151313
NCGC00161599-01
NCGC00161599-02
NCGC00161599-03
Noscal
Parke Davis brand of troglitazone
Prelay
Rezulin
Rezulin (TN)
Romglizone
Romozin
SMP2_000224
Spectrum5_001973
T2573_SIGMA
TROGLITAZONE
Troglitazone (JAN/USAN/INN)
Troglitazone [USAN:BAN:INN]
UPCMLD-DP017
UPCMLD-DP017:001
UPCMLD-DP017:002
Warner-Lambert brand of troglitazone
ATC-Codes:
Side-Effects:
Side-EffectFrequency
hepatitis0
fatigue0
anemia0
congestive heart failure0
syncope0
malaise0
abdominal pain0
fever0
anorexia0
vomiting0
jaundice0
liver function tests abnormal0
nausea0
edema0
weight gain0
hyperglycemia0

Target

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Uniprot ID:CP1A1_HUMAN
Synonyms:
CYPIA1
Cytochrome P450 1A1
P450 form 6
P450-C
P450-P1
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

References:

10534310
Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes.. H Yamazaki; A Shibata; M Suzuki; M Nakajima; N Shimada; F P Guengerich; T Yokoi (1999) Drug metabolism and disposition: the biological fate of chemicals display abstract
Troglitazone, a new oral antidiabetic drug, is reported to be mostly metabolized to its conjugates and not to be oxidized by cytochrome P-450 (P-450) enzymes. Of fourteen cDNA-expressed human P-450 enzymes examined, CYP1A1, CYP2C8, CYP2C19, and CYP3A4 were active in catalyzing formation of a quinone-type metabolite at a concentration of 10 microM troglitazone, whereas CYP3A4 had the highest catalytic activity at 100 microM substrate. In human liver microsomes, rates of the quinone-type metabolite formation (at 100 microM) were correlated well with rates of testosterone 6beta-hydroxylation (r = 0.98), but those at 10 microM troglitazone were not correlated with any of several marker activities of P-450 enzymes. Quercetin efficiently inhibited quinone-type metabolite formation (at 10 microM troglitazone) in human samples that contained relatively high levels of CYP2C, whereas ketoconazole affected these activities in liver microsomes in which CYP3A4 levels were relatively high. Anti-CYP2C antibodies strongly inhibited quinone-type metabolite formation (at 10 microM troglitazone) in CYP2C-rich human liver microsomes (by approximately 85%); the intensity of this effect depended on the human samples and their P-450 status. The results suggest that in human liver both CYP2C8 and CYP3A4 have major roles in quinone-type metabolite formation and that the hepatic contents of these two P-450 forms determine which P-450 enzymes play major roles in individual humans. CYP3A4 may be expected to play a role in formation of quinone-type metabolite from troglitazone even at a low concentration in humans.
15860655
Automated screening with confirmation of mechanism-based inactivation of CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 in pooled human liver microsomes.. Heng-Keang Lim; Nicholas DuczakJr; Linda Brougham; Michael Elliot; Krupa Patel; Kelvin Chan (2005) Drug metabolism and disposition: the biological fate of chemicals display abstract
A strategy is proposed to profile compounds for mechanism-based inactivation of CYP3A4, CYP2C19, CYP2C9, CYP2D6, and CYP1A2 based on an apparent partition ratio screen. Potent positives from the screen are confirmed by time- and concentration-dependent inactivation assays. Quasi-irreversible inhibitions are then differentiated from irreversible inactivations by oxidation with potassium ferricyanide and/or dialysis. The three-step screening procedure has been validated with acceptable accuracy and precision for detection and confirmation of mechanism-based inactivators in drug discovery. We report here the apparent partition ratios for 19 mechanism-based inactivators and four quasi-irreversible inhibitors obtained under the same experimental conditions. The apparent partition ratio screen was automated to provide throughput for determining structure-mechanism-based inactivation relationships. Information about reversibility can be used to assess potential toxicity mediated by covalent adducts, as well as the potential for pharmacokinetic drug-drug interactions. Direct comparison of known mechanism-based inactivators and quasi-irreversible inhibitors, based on our screening of apparent partition ratios, has identified ritonavir, mibefradil, and azamulin as highly effective mechanism-based inactivators; e.g., 1 mol of CYP3A4 was inactivated on turnover of about 2 mol of compound. Other mechanism-based inactivators we identified include bergamottin (CYP1A2 besides previously reported CYP3A4), troglitazone (CYP3A4), rosiglitazone (CYP3A4), and pioglitazone (CYP3A4). Comparison of the apparent partition ratios and inactivation clearance data for the three glitazones suggests that the chromane moiety on troglitazone contributes to its greater potency for mechanism-based inactivation.