Metabolic Activation of a 1,3-Disubstituted Piperazine Derivative: Evidence for a Novel Ring Contraction to an Imidazoline

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• 作者：George A. Doss ; Randall R. Miller ; Zhoupeng Zhang ; Yohannes Teffera ; Ravi P. Nargund ; Brenda Palucki ; Min K. Park ; Yui S. Tang ; David C. Evans ; Thomas A. Baillie ; and Ralph A. Stearns
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：February 2005
• 年：2005
• 卷：18
• 期：2
• 页码：271 - 276
• 全文大小：127K
• 年卷期：v.18,no.2(February 2005)
• ISSN：1520-5010

文摘

MB243 (a 1,3-disubstituted piperazine) is a new, potent, and selective melanocortin receptorsubtype-4 agonist with potential application in the treatment of obesity and/or erectiledysfunction. MB243 was observed to covalently bind extensively to liver microsomal proteinsfrom rats and humans. In the presence of glutathione, two thioether adducts were detected inliver microsomal incubations by radiochromatography and LC/MS/MS analysis. These adductswere also formed when bile duct-cannulated rats were dosed with MB243. The two adductswere isolated, and their structures were determined by accurate mass MS/MS and NMRanalyses. The proposed structures resulted from a novel contraction of the piperazine ring toyield a substituted imidazoline. A mechanism is proposed, which involves an initial six electronoxidation of the piperazine ring to form a reactive intermediate, which is trapped by glutathione.Hydrolysis of the glutamic acid residue followed by internal aminolysis by the cysteine aminogroup resulted in opening of the piperazine ring, which is followed by ring closure to animidazoline. The resulting cysteinyl-glycine conjugate underwent subsequent hydrolysis ofthe glycine residue. Understanding of the mechanism of bioactivation led to the design of MB243analogues that exhibited reduced covalent protein binding.