title: Enantioselective synthesis and teratogenicity of propylisopropyl acetamide, a CNS-active chiral amide analogue of valproic acid.
abstract: Propylisopropyl acetamide (PID), an amide analogue of the major antiepileptic drug valproic acid (VPA), possesses favorable anticonvulsant and CNS properties. PID contains one chiral carbon atom and therefore exists in two enantiomeric forms. The purpose of this work was to synthesize the two PID enantiomers and evaluate their enantiospecific teratogenicity. Enantioselective synthesis of PID enantiomers was achieved by coupling valeroyl chloride with optically pure (4S)- and (4R)-benzyl-2-oxazolidinone chiral auxiliaries. The two oxazolidinone enolates were alkylated with isopropyl triflate, hydrolyzed, and amidated to yield (2R)- and (2S)-PID. These two PID enantiomers were obtained with excellent enantiomeric purity, exceeding 99.4%. Unlike VPA, both (2R)- and (2S)-PID failed to exert teratogenic effects in NMRI mice following a single 3 mmol/kg subcutaneous injection. From this study we can conclude that individual PID enantiomers do not demonstrate stereoselective teratogenicity in NMRI mice. Due to its better anticonvulsant activity than VPA and lack of teratogenicity, PID (in a stereospecific or racemic form) has the potential to become a new antiepileptic and CNS drug.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Spiegelstein
authors.forename: M
authors.initials: M
authors.lastname: Bialer
authors.forename: M
authors.initials: M
authors.lastname: Radatz
authors.forename: H
authors.initials: H
authors.lastname: Nau
authors.forename: B
authors.initials: B
authors.lastname: Yagen
mesh_terms: D000014:Abnormalities, Drug-Induced; D000502:Allylisopropylacetamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000633:toxicity; D005260:Female; D008297:Male; D051379:Mice; D011247:Pregnancy; D013237:Stereoisomerism
chemical_list: D000927:Anticonvulsants; D000502:Allylisopropylacetamide; C009072:propylisopropylacetamide