title: The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus.
abstract: 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. Valnoctamide 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-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. 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 (2S,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, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,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. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Hafiz
authors.initials: H
authors.lastname: Mawasi
authors.affiliation: Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense (MRICD), Aberdeen Proving Ground, MD, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. Electronic address: bialer@md.huji.ac.il.
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000577:Amides / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D013226:Status Epilepticus / Q000188:drug therapy*; D013237:Stereoisomerism; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; C570212:sec-butyl-propylacetamide; C045179:valnoctamide; D014635:Valproic Acid
keywords: Benzodiazepine-resistant status epilepticus; Chiral switch; New antiepileptic drugs; Stereoselective pharmacokinetic and pharmacodynamic analysis