TY - JOUR T1 - Biotransformation of Two <em>β</em>-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1134 LP - 1147 DO - 10.1124/dmd.112.050351 VL - 41 IS - 5 AU - Anders Lindgren AU - Göran Eklund AU - Dominika Turek AU - Jonas Malmquist AU - Britt-Marie Swahn AU - Jörg Holenz AU - Stefan von Berg AU - Sofia Karlström AU - Tjerk Bueters Y1 - 2013/05/01 UR - http://dmd.aspetjournals.org/content/41/5/1134.abstract N2 - Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of β-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings. The main proposed metabolic pathways in various in vitro systems were N-oxidation of the pyridine and/or pyrimidine ring and conversion to 4-pyrimidone and pyrimidine-2,4-dione. Both compounds were extensively metabolized, and more than 90% was excreted in feces after intravenous administration of radiolabeled compound to the rat. Here, the main pathways were N-oxidation of the pyridine and/or pyrimidine ring and a ring contraction of the pyrimidine ring into an imidazole ring. Ring-contracted metabolites accounted for 25% of the total metabolism in the rat for (S)-25, whereas the contribution was much smaller for AZD3839. This metabolic pathway was not foreseen on the basis of the obtained in vitro data. In conclusion, we discovered an unusual metabolic pathway of aryl-pyrimidine–containing compounds by a ring-opening reaction followed by elimination of a carbon atom and a ring closure to form an imidazole ring. ER -