Stereoselective Pharmacodynamic and Pharmacokinetic Analysis of sec-Butylpropylacetamide (SPD), a New CNS-Active Derivative of Valproic Acid with Unique Activity against Status Epilepticus

Abstract

sec-Butylpropylacetamide (racemic-SPD) is a chiral CNS-active amide derivative of valproic acid (VPA). This study describes synthesis and stereospecific comparative pharmacodynamics (PD, anticonvulsant activity and teratogenicity) and pharmacokinetic (PK) analysis of four individual SPD stereoisomers. SPD stereoisomers' anticonvulsant activity was comparatively evaluated in several anticonvulsant animal models including the benzodiazepine-resistant status epilepticus (SE). SPD stereoisomers' PK-PD relationship was evaluated in rats. Teratogenicity of SPD stereoisomers was evaluated in SWV mice strain, susceptible to VPA-induced neural tube defect (NTD). SPD stereoisomers (141 or 283 mg/kg) did not cause NTD. SPD has stereoselective PK and PD. (2R,3S)-SPD and (2S,3R)-SPD higher clearance led to a 50% lower plasma exposure that may contribute to their relative lower activity in the pilocarpine-induced SE model. (2S,3S)-SPD, (2R,3R)-SPD, and racemic-SPD have similar anticonvulsant activity and a PK profile that are better than those of (2R,3S)-SPD and (2S,3R)-SPD, making them good candidates for development as new, potent antiepileptics with a potential in benzodiazepine-resistant SE.

Pharmacodynamic and pharmacokinetic analysis of CNS-active constitutional isomers of valnoctamide and sec-butylpropylacetamide — Amide derivatives of valproic acid

“…The PK parameters of SID, TED, and TID were calculated by noncompartmental analysis based on statistical moment theory using PK software Phoenix Winnonlin Tripos L.P. version 6.3 (Pharsight Co., Mountain View, CA) as previously described [7,9,14].…”

“…However, in contrast to its one-carbon homologue, SPD, VCD lost its behavioral SE protection when administered (80 mg/kg) 30 min after seizure onset [14], but it did block pilocarpine-induced electrographic SE at a higher dose (180 mg/kg) [8]. Following a single dose (600 mg/kg, ip) at day 8.5 of gestation, VCD and SPD and their individual stereoisomers failed to exert any significant teratogenic effect in Swiss Vancouver (SWV)/Fnn mice, an inbred mouse strain that is highly susceptible to VPA-induced teratogenicity [9,14].…”

“…sec-Butylpropylacetamide (SPD, Fig. 1) is a one-carbon homologue of VCD currently in the preclinical stage that has unique activity against status epilepticus and organophosphate neuronal damage [7][8][9]. Both VCD and SPD ( Fig.…”

“…Racemic VCD and racemic SPD have a wide spectrum of anticonvulsant activity, and their ED 50 values are 2-16 times (depending on the model) more potent than those of VPA [7,9,[13][14][15]. Valnoctamide (65 mg/kg, ip) also provided a full protection in the pilocarpineinduced status epilepticus (SE) rat model when administered at seizure onset.…”

“…All studies so far have focused on VCD and SPD and their individual stereoisomers [7,9,13,14]. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three constitutional isomers of SPD [secbutylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)] and of VCD [tert-butylethylacetamide (TED)].…”