title: 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.
authors.affiliation: Institute for Drug Research, Faculty of Medicine, School of Pharmacy, The Hebrew University of Jerusalem, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Hen
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000577:Amides; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051381:Rats; D012999:Soman / Q000037:antagonists & inhibitors; D013226:Status Epilepticus / Q000188:drug therapy*; D013237:Stereoisomerism; D013723:Teratogens / Q000633:toxicity; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use* / Q000031:analogs & derivatives
chemical_list: D000081:Acetamides; D000577:Amides; D000927:Anticonvulsants; D013723:Teratogens; C570212:sec-butyl-propylacetamide; D014635:Valproic Acid; D012999:Soman