The metabolism of acetamidothiazoles in the rat. 2-Acetamido-, 2-acetamido-4-methyl- and 2-acetamido-4-phenyl-thiazole

Chatfield, David H.; Hunter, W. H.

doi:10.1042/bj1340869

Cited by 16 publications

(12 citation statements)

References 8 publications

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“…The thioformamide thus formed is believed to be the proximate toxicant derived from thiabendazole [313]. Additional examples of biologically-active thiazoles that undergo ring opening (see Figure 49) include the immunomodulatory agent SM-8849 [314], the NSAID sudoxicam [315], anti-inflammatory 2-acetylaminothiazoles [316] and the hepatoprotective agent YH-439 [317]. The NSAID sudoxicam has been withdrawn from the market due to hepatotoxic consequences, a phenomenon that has been linked to the thiazole ring scission observed during the metabolism of this compound.…”

Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

View full text Add to dashboard Cite

show abstract

“…In the preceding paper we described studies on the metabolism and excretion, by the rat, of some 4substituted 2-acetamidothiazoles (Chatfield & Hunter, 1973). These compounds were part of a series of anti-inflammatory compounds (Evans, 1972) of which the most active member was the 4-chloromethyl compound (I).…”

mentioning

confidence: 99%

The metabolism of acetamidothiazoles in the rat. 2-Acetamido-4-chloromethylthiazole

Chatfield

Hunter

1973

Biochemical Journal

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2-Acetamido-4-chloromethylthiazole is metabolized in the rat to (2-acetamido-4-thiazolylmethyl)mercapturic acid and 2-acetamidothiazole-4-carboxylic acid. 2-Acetamido-4-methylthiomethylthiazole and the corresponding sulphoxide and sulphone are also produced as minor metabolites. The identification of the metabolites is described and their formation investigated. Quantitative results on the excretion of the metabolites labelled with (14)C are reported.

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“…Mizutani (1993Mizutani ( , 1994 and Mizutani and Suzuki (1996) reported that epoxidation of the C4-C5 double bond and subsequent ring scission of substituted thiazoles results in the formation of the corresponding -dicarbonyl metabolites and thioamide derivatives. Similar thiazole ring scission has also been observed in metabolism studies with the immunomodulatory agent SM-8849 (Yabuki et al 1997) and anti-inflammatory 2-acetylaminothiazoles (Chatfield and Hunter 1973). The hepatoprotective agent YH-439 (Yoon et al 1998) undergoes thiazole hydroxylation at the C5 position by cytochrome P450, followed by thiazole ring opening between the sulfur and the C5 by esterases, forming metabolites containing carbonthionyl and the acid.…”

Section: Discussionmentioning

confidence: 80%

In vitromicrosomal metabolic studies on a selective mGluR5 antagonist MTEP: Characterization ofin vitrometabolites and identification of a novel thiazole ring opening aldehyde metabolite

Yang

2005

Xenobiotica

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In vitro liver microsomal studies revealed that [14C] MTEP (3-[2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine) was metabolized into three major oxidative metabolites. Metabolite 1 (M1) was shown to be a hydroxymethyl metabolite; M2 was shown to be a pyridine oxide. Moreover, a novel aldehyde metabolite (M3) was identified from mouse liver microsomes. The structure of the aldehyde M3 was elucidated by LC/MS/MS. In addition, methoxyamine, an aldehyde-trapping agent, and accurate mass measurement using a high-resolution quadrupole-time of flight (Q-TOF) instrument, were used to confirm the proposed thiazole ring-opening structure of M3. A mechanism for aldehyde M3 formation was postulated based on MTEP incubation studies with 18O2 and H2 18O using mouse liver microsomes. MTEP was initially oxidized at sulfur, followed by subsequent C4-C5 of thiazole epoxidation, thiozole ring opening and further oxidative desulfation. This proposed thiazole ring-opening mechanism might represent a novel metabolism pathway for xenobiotics containing a thiazole moiety. Species differences in the metabolism of MTEP were observed in mouse, rat, dog, monkey and human liver microsomes. Mouse appears to generate all three oxidative metabolites to a greater extent than other species examined.

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The metabolism of acetamidothiazoles in the rat. 2-Acetamido-, 2-acetamido-4-methyl- and 2-acetamido-4-phenyl-thiazole

Cited by 16 publications

References 8 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

The metabolism of acetamidothiazoles in the rat. 2-Acetamido-4-chloromethylthiazole

In vitromicrosomal metabolic studies on a selective mGluR5 antagonist MTEP: Characterization ofin vitrometabolites and identification of a novel thiazole ring opening aldehyde metabolite

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