Haloarene Derivatives of Carbamazepine with Reduced Bioactivation Liabilities: 2‑Monohalo and 2,8-Dihalo Derivatives
journal contributionposted on 26.11.2012, 00:00 authored by Emma-Claire Elliott, Sophie L. Regan, James L. Maggs, Elizabeth R. Bowkett, Laura J. Parry, Dominic P. Williams, B. Kevin Park, Andrew V. Stachulski
The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.