title: Biotransformation of two β-secretase inhibitors including ring opening and contraction of a pyrimidine ring.
abstract: 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Södertälje, Sweden. alindgren800@gmail.com
authors.forename: Anders
authors.initials: A
authors.lastname: Lindgren
authors.forename: Göran
authors.initials: G
authors.lastname: Eklund
authors.forename: Dominika
authors.initials: D
authors.lastname: Turek
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmquist
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Stefan
authors.initials: S
authors.lastname: von Berg
authors.forename: Sofia
authors.initials: S
authors.lastname: Karlström
authors.forename: Tjerk
authors.initials: T
authors.lastname: Bueters
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D002853:Chromatography, Liquid; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics; D008297:Male; D013058:Mass Spectrometry; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C578092:AZD3839; D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D053829:Amyloid Precursor Protein Secretases; C030986:pyrimidine