The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus

sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamicle has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset sec-Butylpropylacetamicle and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four stereoisorners. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (25,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (25,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (25,3R)-SPD.Valnoctamide has a stereoselective PK with (25,3S)-VCD exhibiting the lowest clearance and, consequently, a twice higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. se c-Bulylpr up y la cc L a mide and VCD stereoisomers did not cause leratogenicily (i.e., neural rube defect) in mice al doses 3-12 times higher than their anticonvulsant-ED50 values. 2015 Elsevier Inc. All rights reserved.