OBJECTIVE: Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. METHODS: The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. RESULTS: VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3-12 times higher than VCD anticonvulsant ED50 values. SIGNIFICANCE: VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs. Wiley Periodicals, Inc.
OBJECTIVE:Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. METHODS: The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. RESULTS:VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3-12 times higher than VCD anticonvulsant ED50 values. SIGNIFICANCE: VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs. Wiley Periodicals, Inc.
Authors: Meir Bialer; Svein I Johannessen; René H Levy; Emilio Perucca; Torbjörn Tomson; H Steve White Journal: Epilepsy Res Date: 2010-12 Impact factor: 3.045
Authors: H Steve White; Anitha B Alex; Amanda Pollock; Naama Hen; Tawfeeq Shekh-Ahmad; Karen S Wilcox; John H McDonough; James P Stables; Dan Kaufmann; Boris Yagen; Meir Bialer Journal: Epilepsia Date: 2011-12-09 Impact factor: 5.864
Authors: W Pouliot; M Bialer; N Hen; T Shekh-Ahmad; D Kaufmann; B Yagen; K Ricks; B Roach; C Nelson; F E Dudek Journal: Neuroscience Date: 2012-11-14 Impact factor: 3.590
Authors: Naama Hen; Tawfeeq Shekh-Ahmad; Boris Yagen; John H McDonough; Richard H Finnell; Bogdan Wlodarczyk; Meir Bialer Journal: J Med Chem Date: 2013-08-07 Impact factor: 7.446
Authors: Sara Ornaghi; Lawrence S Hsieh; Angélique Bordey; Patrizia Vergani; Michael J Paidas; Anthony N van den Pol Journal: J Neurosci Date: 2017-06-19 Impact factor: 6.167
Authors: Kari M Haines; Liana M Matson; Emily N Dunn; Cherish E Ardinger; Robyn Lee-Stubbs; David Bibi; John H McDonough; Meir Bialer Journal: Epilepsia Date: 2019-01-07 Impact factor: 5.864
Authors: Sara Ornaghi; John N Davis; Kelly L Gorres; George Miller; Michael J Paidas; Anthony N van den Pol Journal: Virology Date: 2016-09-19 Impact factor: 3.616
Authors: Alexei P Kudin; Hafiz Mawasi; Arik Eisenkraft; Christian E Elger; Meir Bialer; Wolfram S Kunz Journal: Int J Mol Sci Date: 2017-09-06 Impact factor: 5.923
Authors: Richard H Finnell; Carlo Donato Caiaffa; Sung-Eun Kim; Yunping Lei; John Steele; Xuanye Cao; Gabriel Tukeman; Ying Linda Lin; Robert M Cabrera; Bogdan J Wlodarczyk Journal: Front Genet Date: 2021-05-10 Impact factor: 4.599