Haloarene Derivatives of Carbamazepine with Reduced Bioactivation Liabilities: 2‑Monohalo and 2,8-Dihalo Derivatives

• Published in: Journal of medicinal chemistry Vol. 55; no. 22; pp. 9773 - 9784
• Main Authors: Elliott, Emma-Claire, Regan, Sophie L, Maggs, James L, Bowkett, Elizabeth R, Parry, Laura J, Williams, Dominic P, Park, B. Kevin, Stachulski, Andrew V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.11.2012; Amer Chemical Soc
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacology; Carbamazepine - analogs & derivatives; Carbamazepine - pharmacology; Cells, Cultured; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Chromatography, Liquid; Glutathione - metabolism; Halogens - chemistry; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Life Sciences & Biomedicine; Male; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Structure; Oxidation-Reduction; Pharmacology & Pharmacy; Rats; Rats, Wistar; Science & Technology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure-Activity Relationship; REVERSE-TRANSCRIPTASE INHIBITOR; PATHWAYS; IN-VITRO; REACTIVE METABOLITES; N-GLUCURONIDES; SPECIES-DIFFERENCES; HUMAN CYTOCHROME-P450 ENZYMES; URINARY METABOLITES; ACYL GLUCURONIDE; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301013n

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.