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Xenobiotica
the fate of foreign compounds in biological systems
Volume 37, 2007 - Issue 9
152
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Research Article

Studies of metabolism and disposition of potent human immunodeficiency virus (HIV) integrase inhibitors using 19F-NMR spectroscopy

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Pages 1000-1012 | Received 24 Aug 2007, Accepted 28 Aug 2007, Published online: 22 Sep 2008
 

Abstract

19F-nuclear magnetic resonance (NMR) has been extensively used in a drug-discovery programme to support the selection of candidates for further development. Data on an early lead compound, N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (compound A (+)), and MK-0518 (N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide), a potent inhibitor of this series currently in phase III clinical trials, are described. The metabolic fate and excretion balance of compound A (+) and MK-0518 were investigated in rats and dogs following intravenous and oral dosing using a combination of 19F-NMR-monitored enzyme hydrolysis and solid-phase extraction chromatography and NMR spectroscopy (SPEC-NMR). Dosing with the 3H-labelled compound A (+) enabled the comparison of standard radiochemical analysis with 19F-NMR spectroscopy to obtain quantitative metabolism and excretion data. Both compounds were eliminated mainly by metabolism. The major metabolite identified in rat urine and bile and in dog urine was the 5-O-glucuronide.

Acknowledgements

The authors thank Odalys Gonzalez-Paz, Fabio Bonelli, Francesca Naimo, Maria Verdirame, and Massimiliano Fonsi for pharmacokinetics and analytical support. They also thank Frank Tang (Merck Research Laboratories, Rahway, NJ, USA) for radiochemical synthesis of tritiated compound A (+). This work was supported in part by a grant from the Ministero dell’Istruzione, dell’Università e della Ricerca.

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