Strategies to prevent N-acetyltransferase-mediated metabolism in a series of piperazine-containing pyrazalopyrimidine compounds

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
J RawalI Gardner

Abstract

1. (1-Methyl-5-piperazine-1-yl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(5-methyl-pyridin-2-yl)-amine (UK-469,413) was identified as a lead compound in a new medicinal chemistry programme. UK-469,413 had good physicochemical properties and was slowly metabolized by cytochromes P450 in rat and human liver microsomes. 2. In the rat in vivo the compound was rapidly cleared. Subsequent studies showed that UK-469,413 was rapidly acetylated in rat liver cytosol to an N-acetylpiperazine metabolite that was the major circulating metabolite in rat plasma in vivo. 3. Analogues of UK-469,413 containing the unsubstituted piperazine moiety were rapidly acetylated in rat liver cytosol and had high plasma clearance in the rat in vivo. These compounds were also acetylated in human liver cytosol and the N-acetyl metabolite was a major metabolite formed in incubations with cryopreserved human hepatocytes. 4. Using specific inhibitors, correlation analysis and expressed human N-acetyltransferase (NAT) enzymes the compounds were shown to be substrates of the polymorphically expressed NAT-2 isozyme. 5. Further experiments showed that it was possible to make small structural changes to the piperazine group that retained potency but prevented metab...Continue Reading

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Citations

Jun 10, 2014·Drug Metabolism Reviews·Jayaprakasam BolleddulaDavid L Bourdet
Jun 24, 2010·Bioorganic & Medicinal Chemistry Letters·David S CarterRobert J Weikert
Apr 19, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nathalie RiouxNigel J Waters
Jun 17, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Q SunP Marathe

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