Genotoxicity of 2-(3-Chlorobenzyloxy)-6-(piperazinyl)pyrazine, a Novel 5-Hydroxytryptamine2c Receptor Agonist for the Treatment of Obesity: Role of Metabolic Activation

  title={Genotoxicity of 2-(3-Chlorobenzyloxy)-6-(piperazinyl)pyrazine, a Novel 5-Hydroxytryptamine2c Receptor Agonist for the Treatment of Obesity: Role of Metabolic Activation},
  author={Amit S. Kalgutkar and Deepak K. Dalvie and Jiri Aubrecht and Evan B. Smith and Stephanie L. Coffing and Jennifer R. Cheung and Chandra Vage and Mary E. Lame and Phoebe Chiang and Kim F McClure and Tristan S. Maurer and Richard V Coelho and Victor F. Soliman and Klaas Schildknegt},
  journal={Drug Metabolism and Disposition},
  pages={848 - 858}
2-(3-Chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine (3) is a potent and selective 5-HT2C agonist that exhibits dose-dependent inhibition of food intake and reduction in body weight in rats, making it an attractive candidate for treatment of obesity. However, examination of the genotoxicity potential of 3 in the Salmonella Ames assay using tester strains TA98, TA100, TA1535, and TA1537 revealed a metabolism (rat S9/NADPH)- and dose-dependent increase of reverse mutations in strains TA100 and TA1537… 

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