Teratology Study of Amide Derivatives of Branched Aliphatic Carboxylic Acids with 4‐Aminobenzensulfonamide in NMRI Mice

Abstract

BACKGROUNDValproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2‐methyl‐N‐(4‐sulfamoyl‐phenyl)‐pentanamide (MSP), 2‐ethyl‐N‐(4‐sulfamoyl‐phenyl)‐butyramide (ESB), 2‐ethyl‐4‐methyl‐N‐(4‐sulfamoyl‐phenyl)‐pentanamide (EMSP), and 2‐ethyl‐N‐(4‐sulfamoyl‐benzyl)‐butyramide (ESBB), have shown more potent anticonvulsant activity than VPA in preclinical testing. Here, we investigated the teratogenic effects of these analogous compounds of VPA in NMRI mice.METHODSPregnant NMRI mice were given a single subcutaneous injection of either VPA at 1.8 or 3.6 mmol/kg, or MSP, ESB, EMSP, or ESBB at 1.8, 3.6, or 4.8 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18, and the live fetuses were examined for external and skeletal malformations.RESULTSCompared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at dose levels up to 4.8 mmol/kg (except for a single case of exencephaly at 4.8 mmol/kg MSP). Skeletal examination showed several abnormalities mainly at the axial skeletal level with VPA at 1.8 mmol/kg. Fused vertebrae and/or fused ribs were also observed with MSP, ESB, EMSP, and ESBB, they were less severe and seen at a lower incidence that those induced by VPA at the same dose level.CONCLUSIONSIn addition to exerting more potent preclinical antiepileptic activity, teratology comparison indicates that aminobenzensulfonamide analogs are generally more weakly teratogenic than VPA.