IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-<i>N</i>-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

Karanam, Bindhu V.; Hop, Cornelis E. C. A.; Liu, David Q.; Wallace, Mike; Dean, Dennis C.; Satoh, H; Komuro, Masakatsu; Awano, Katsuya; Vincent, Stella

doi:10.1124/dmd.104.000034

Cited by 20 publications

(10 citation statements)

References 22 publications

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“…Interestingly, P450 2C9 represents an enzyme involved in the metabolism of PPAR ligands [28]. Moreover, the six models for the P450 2C9 target comprised in the Inte:Ligand database are not as restrictive as our PPAR models, because the P450 2C9 hypotheses were made to accommodate a highly diverse set of ligands which are metabolized by this enzyme [29].…”

Section: B Resultsmentioning

confidence: 99%

Pharmacophore modeling and parallel screening for PPAR ligands

Markt

Schuster

Kirchmair

et al. 2007

J Comput Aided Mol Des

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We describe the generation and validation of pharmacophore models for PPARs, as well as a large scale validation of the parallel screening approach by screening PPAR ligands against a large database of structure-based models. A large test set of 357 PPAR ligands was screened against 48 PPAR models to determine the best models for agonists of PPAR-alpha, PPAR-delta, and PPAR-gamma. Afterwards, a parallel screen was performed using the 357 PPAR ligands and 47 structure-based models for PPARs, which were integrated into a 1537 models comprising in-house pharmacophore database, to assess the enrichment of PPAR ligands within the PPAR hypotheses. For these purposes, we categorized the 1537 database models into 181 protein targets and developed a score that ranks the retrieved targets for each ligand. Thus, we tried to find out if the concept of parallel screening is able to predict the correct pharmacological target for a set of compounds. The PPAR target was ranked first more often than any other target. This confirms the ability of parallel screening to forecast the pharmacological active target for a set of compounds.

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Section: B Resultsmentioning

confidence: 99%

Pharmacophore modeling and parallel screening for PPAR ligands

Markt

Schuster

Kirchmair

et al. 2007

J Comput Aided Mol Des

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“…Several in vitro and in vivo studies have shown that the TZD ring of various glitazones such as troglitazone 21a, MK-0767 21b, and MRL-A 21c (Fig. 10), was subject to an oxidative metabolism resulting in its opening with formation of reactive metabolites [33][34]. A detailed study of the metabolites derived from the oxidation of the TZD ring of 21c by monkey liver microsomes in the presence of NADPH showed the formation of several compounds that should derive from sulfenic acid 22c [34] (Fig.…”

Section: Recent Evidence For the Formation Of Sulfenic Acid Reactive mentioning

confidence: 99%

“…The fates of the intermediate sulfenic acids were similar for the two series of drugs, with the formation of the corresponding thiols and glutathione mixed disulfide adducts in both cases. The main difference was concerned with the formation of a sulfinic acid derived from glitazones [33,34] that has not been observed so far in the case of the tetrahydrothienopyridine drugs.…”

Section: Recent Evidence For the Formation Of Sulfenic Acid Reactive mentioning

confidence: 99%

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Mansuy

Dansette

2011

Archives of Biochemistry and Biophysics

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Sulfenic acid reactive intermediates are formed during the oxidation of cysteine residues of proteins and play key roles in enzyme catalysis, redox homeostasis and regulation of cell signalling. However few data are presently available on the formation and fate of sulfenic acids as reactive intermediates during the metabolism of xenobiotics. This article is a review of the xenobiotic metabolism situations in which the intermediate formation of a sulfenic acid has been reported. Formation of these intermediates has been either proposed on the basis of the isolation of products possibly deriving from sulfenic acids or shown after trapping of the sulfenic acid by specific nucleophiles. This review indicates the different mechanisms by which a sulphur-containing xenobiotic can be metabolized with the intermediate formation of a sulfenic acid. It also indicates the different possible fates of these sulfenic acids that have been reported in the literature. Finally, it discusses the possible implications of the formation of xenobiotic-derived sulfenic acid reactive metabolites in pharmacology and toxicology.

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“…Moreover, S‐oxidation of the TZD ring of troglitazone21 and MK0767 (V. Reddy et al, in preparation) has been implicated in the ring scission observed to occur enzymatically under oxidative conditions. In nonclinical species and humans, the major metabolism pathway for MK‐0767 is believed to proceed via S‐oxidation followed by TZD cleavage and reduction and further methylation and oxidation 22, 23…”

Section: Resultsmentioning

confidence: 99%

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Shen

Bakhtiar

Komuro

et al. 2005

Rapid Comm Mass Spectrometry

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MK-0767, (+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide, is a thiazolidinedione-containing dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist that has been studied as a potential treatment for patients with type 2 diabetes. MK-0767 contains a chiral center at the C-5 position of the thiazolidinedione ring and was being developed as the racemate, due to the rapid interconversion of its enantiomers in biological samples. In the present work the in vitro and in vivo concentration ratios of the (+)-(R) to (-)-(S) enantiomers of MK-0767 were determined in plasma from humans (in vitro only) and nonclinical species used in the toxicological evaluation of rac-MK-0767, namely CD-1 mice, Sprague-Dawley rats, beagle dogs, New Zealand white rabbits, and rhesus monkeys. The R/S ratio was determined by chiral liquid chromatography/tandem mass spectrometry. Species differences were observed in the in vitro and in vivo enantiomeric ratios, as well as differences between in vitro and in vivo in some species. The in vitro R/S ratio was similar in dogs and humans (approximately 1.5-1.7). In rats and monkeys, the ratio was approximately unity, both in vitro and in vivo. In mice, the ratio was higher in vitro (approximately 1) than in vivo (approximately 0.6), while in rabbits it was higher in vivo (approximately 1) than in vitro (approximately 0.5). These results suggested that differential binding of the MK-0767 enantiomers to plasma and tissue proteins and other macromolecules may be affecting the R/S ratio both in vitro and in vivo, since in protein-free systems MK-0767 exists as the racemate.

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IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

Cited by 20 publications

References 22 publications

Pharmacophore modeling and parallel screening for PPAR ligands

Pharmacophore modeling and parallel screening for PPAR ligands

Sulfenic acids as reactive intermediates in xenobiotic metabolism

Enantiomer ratio of MK‐0767 in humans and nonclinical species

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