Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.

Abstract

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.

• Authors: Tawfeeq Shekh-Ahmad, Naama Hen, Boris Yagen, John H McDonough, Richard H Finnell, Bogdan J Wlodarczyk, Meir Bialer
• Journal: Epilepsia (Epilepsia) Vol. 55 Issue 2 Pg. 353-61 (Feb 2014) ISSN: 1528-1167 [Electronic] United States
• PMID: 24313671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Chemical References

• Amides
• Anticonvulsants
• Central Nervous System Stimulants
• Teratogens
• valnoctamide
• Valproic Acid

Topics

• Amides (chemistry, pharmacokinetics, toxicity)
• Animals
• Anticonvulsants (chemistry, pharmacokinetics, toxicity)
• Central Nervous System Stimulants (chemistry, pharmacokinetics, toxicity)
• Male
• Mice
• Neural Tube Defects (chemically induced)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Status Epilepticus (chemically induced, prevention & control)
• Stereoisomerism
• Teratogens (chemistry, pharmacokinetics, toxicity)
• Valproic Acid (chemistry, pharmacokinetics, toxicity)