Characterization of the in vitro oxidative metabolites of the COX-2 selective inhibitor L-766,112

Trimble, Laird A.; Chauret, Nathalie; Silva, JoséM; Nicoll‐Griffith, Deborah A.; Li, Chun‐Sing; Yergey, James A.

doi:10.1016/s0960-894x(96)00581-1

Cited by 21 publications

(16 citation statements)

References 6 publications

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“…5), similar to one discerned with the imidazo[2,1-b]-thiazole derivative L-766,112 (Trimble et al, 1997). To distinguish between the two possibilities, a H-13 C HSQC spectrum of M3-1 are more consistent with the structure resulting from the S-oxidation pathway and are also closely aligned with the NMR data reported for the GSH conjugate of L-766,112 S-oxide (Trimble et al, 1997). Furthermore, the TOCSY data set (Fig.…”

Section: Resultsmentioning

confidence: 58%

“…There are two obvious pathways through which this can arise, either via a P450-mediated epoxidation at the C4-C5 position of the thiazole ring with addition of GSH or through a P450-mediated S-oxidation of the thiazole sulfur followed by addition of GSH to the S-oxide metabolite (structure depicted in Fig. 5), similar to one discerned with the imidazo[2,1-b]-thiazole derivative L-766,112 (Trimble et al, 1997). To distinguish between the two possibilities, a H-13 C HSQC spectrum of M3-1 are more consistent with the structure resulting from the S-oxidation pathway and are also closely aligned with the NMR data reported for the GSH conjugate of L-766,112 S-oxide (Trimble et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

“…The otherwise attractive pharmacological and pharmacokinetic attributes of ghrelin inverse agonists 1 and 2 were offset by the presence of the imidazo[2,1-b]thiazole bicycle as part of the core structure, especially in light of previous studies by Trimble et al (1997) who demonstrated the microsomal S-oxidation of the thiazole portion (within the bicycle) to an electrophilic sulfoxide metabolite that underwent a 1,4-Michael addition reaction with GSH. In addition, evidence linking thiazole ring bioactivation with preclinical (or clinical) toxicity has been presented for several thiazole-based xenobiotics and drugs (Kalgutkar et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…An alternate pathway that leads to M3-1 involves P450-mediated oxidation on the thiazole sulfur to the S-oxide metabolite M5-1, followed by the Michael addition of GSH to yield adduct M3-1 (see Fig. 15, pathway B) as outlined previously with the imidazo[2,1-b]thiazole analog L-766,112 (Trimble et al, 1997). NMR analysis of the crude M3-1 isolate indicated that the GSH adduct was derived from addition of the thiol nucleophile to the electrophilic S-oxide M5-1 and not from the ring opening of epoxide 12.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the characterization of a GSH conjugate derived from Michael addition to an S-oxide metabolite of the imidazo [2,1-b] -766,112) (Fig. 1) provides precedence for this bioactivation pathway in liver microsomes (Thérien et al, 1997;Trimble et al, 1997). Furthermore, a successful medicinal chemistry strategy involving internalization of the thiazole motif, resulting in the elimination of reactive metabolite liability of L-766,112, while retaining the primary pharmacology (selective inhibition of cyclooxygenase-2) has been presented in subsequent work ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

Kalgutkar

Ryder

Walker

et al. 2013

Drug Metabolism and Disposition

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The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(2-methylimidazo[2,1-b]thiazol-6-yl) ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18 O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield 2-,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.

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Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

Kalgutkar

Ryder

Walker

et al. 2013

Drug Metabolism and Disposition

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Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities. However, in some cases, these reactions can convert drugs to products that are either chemically reactive or pharmacologically active, a process that is commonly referred to as metabolic activation or bioactivation . Most, if not all, functionalization and conjugation reactions can result in bioactivation. Even though all enzymes have the propensity to catalyze the metabolic activation of compounds, cytochrome P450 (P450) enzymes, which generally dominate metabolism, play a major role in the metabolic activation of drugs. The primary objective of this chapter is to provide an overview of bioactivation by P450 to pharmacologically active and chemically reactive metabolites. The common reactions that result in bioactivation of xenobiotics and consequences of bioactivation have been discussed here.

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Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry

Kalgutkar

2011

Mass Spectrometry in Drug Metabolism and Disposition

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Characterization of the in vitro oxidative metabolites of the COX-2 selective inhibitor L-766,112

Cited by 21 publications

References 6 publications

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

Bioactivation I: Bioactivation by Cytochrome P450s

Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry

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