Abstract | PURPOSE: METHODS: Compounds were synthesized from their corresponding acids. The induction of neural tube defects ( exencephaly) of the resulting hydroxamates (applied on day 8.25 of gestation) was tested in the offspring of pregnant animals (Han:NMRI mice). The anticonvulsant activity was evaluated in the subcutaneous pentylenetetrazole (PTZ) seizure threshold test and neurotoxicity in the rotorod neurotoxicity test. RESULTS: All tested hydroxamates showed no or greatly reduced teratogenic potency in mice compared to the free acids. Furthermore all compounds exhibited anticonvulsant activity with ED(50) doses ranging from 0.16 mmol/kg to 0.59 mmol/kg (VPA 0.57 mmol/kg). Neurotoxicity of the hydroxamates was increased compared to VPA. TD(50) doses range from 0.70 mmol/kg to 1.42 mmol/kg (VPA 1.83 mmol/kg). CONCLUSION:
Hydroxamic acid derivatives of VPA with improved protective index and little or undetectable teratogenic potency compared to the free acids are described. alpha-fluorination of VPA also resulted in loss of teratogenic activity. Such fluorination of the hydroxamic acids also led to compounds with an improved anticonvulsant profile compared to non-fluorinated hydroxamates. The non-chiral 2-Fluoro-VPA-hydroxamic acid was the most promising compound with a protective index (ratio of TD(50) to ED(50)) of 4.4 compared to 3.2 for VPA. This compound combines an improved ratio of anticonvulsant potency/neurotoxicity with the advantage of not being teratogenic in the mouse neural tube defect model used.
|
Authors | Ute Gravemann, Jutta Volland, Heinz Nau |
Journal | Neurotoxicology and teratology
(Neurotoxicol Teratol)
2008 Sep-Oct
Vol. 30
Issue 5
Pg. 390-4
ISSN: 0892-0362 [Print] United States |
PMID | 18455366
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Anticonvulsants
- Convulsants
- Hydrocarbons, Fluorinated
- Hydroxamic Acids
- Teratogens
- Valproic Acid
|
Topics |
- Animals
- Anticonvulsants
(chemical synthesis, toxicity)
- Convulsants
(pharmacology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
(methods)
- Epilepsy
(chemically induced, drug therapy, physiopathology)
- Female
- Hydrocarbons, Fluorinated
(toxicity)
- Hydroxamic Acids
(toxicity)
- Mice
- Molecular Structure
- Neural Tube Defects
(chemically induced)
- Pregnancy
- Prenatal Exposure Delayed Effects
(chemically induced, physiopathology)
- Structure-Activity Relationship
- Teratogens
(chemical synthesis, toxicity)
- Toxicity Tests
- Valproic Acid
(analogs & derivatives, chemical synthesis, toxicity)
|