title: Haloarene derivatives of carbamazepine with reduced bioactivation liabilities: 2-monohalo and 2,8-dihalo derivatives.
abstract: 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.
authors.affiliation: Department of Chemistry,  University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Emma-Claire
authors.initials: EC
authors.lastname: Elliott
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Regan
authors.forename: James L
authors.initials: JL
authors.lastname: Maggs
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Bowkett
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Parry
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Stachulski
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005978:Glutathione / Q000378:metabolism; D006219:Halogens / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D006219:Halogens; D002220:Carbamazepine; D005978:Glutathione