Preclinical profiling and safety studies of ABT-769: a compound with potential for broad-spectrum antiepileptic activity.

Abstract

PURPOSE:

The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide].

METHODS:

ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse.

RESULTS:

ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects.

CONCLUSIONS:

ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.

• Authors: William J Giardina, Michael J Dart, Richard R Harris, Robert S Bitner, Richard J Radek, Gerard B Fox, Sanjay R Chemburkar, Kennan C Marsh, Jeffrey F Waring, Julia Y Hui, Jinhua Chen, Peter Curzon, George K Grayson, Victoria A Komater, Yiyin Ku, Mark Lockwood, Holly M Miner, Arthur L Nikkel, Jia Bao Pan, Yu-Ming Pu, Lei Wang, Youssef Bennani, Niklaus Durmuller, Robert Jolly, Sylvain Roux, James P Sullivan, Michael W Decker
• Journal: Epilepsia (Epilepsia) Vol. 46 Issue 9 Pg. 1349-61 (Sep 2005) ISSN: 0013-9580 [Print] United States
• PMID: 16146429 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ABT-769
• Anticonvulsants
• Spiro Compounds
• Valproic Acid
• Pentylenetetrazole

Topics

• Abnormalities, Drug-Induced (epidemiology)
• Amygdala (drug effects, physiopathology)
• Animals
• Anticonvulsants (pharmacology, toxicity)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Electroshock
• Epilepsy (chemically induced, metabolism, prevention & control)
• Epilepsy, Absence (chemically induced, metabolism, prevention & control)
• Humans
• Injections, Intravenous
• Injections, Subcutaneous
• Kindling, Neurologic (drug effects, metabolism, physiology)
• Male
• Mice
• Mitochondria, Liver (drug effects, metabolism)
• Pentylenetetrazole (administration & dosage)
• Rats
• Rats, Wistar
• Species Specificity
• Spiro Compounds (pharmacology, toxicity)
• Valproic Acid (analogs & derivatives, pharmacology, toxicity)