α-Fluoro-2,2,3,3-Tetramethylcyclopropanecarboxamide, a Novel Potent Anticonvulsant Derivative of a Cyclic Analogue of Valproic Acid

Abstract

2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). alpha-F, alpha-Cl, alpha-Br, and alpha-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, alpha-Cl-TMCD (17) had ED(50) values of 97 and 27 mg/kg, respectively. alpha-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED(50) = 6 mg/kg) and had a protective index (PI = TD(50)/ED(50)) of 20. In the 6 Hz psychomotor mouse model 11 had ED(50) values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED(50) values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.

Comparative pharmacodynamic and pharmacokinetic analysis of two anticonvulsant halo derivatives of 2,2,3,3‐tetramethylcyclopropanecarboxamide, an amide of a cyclic analog of valproic acid

“…The quantitative anticonvulsant activity (ED 50 ) of α‐F‐TMCD in rats and mice, and the qualitative anticonvulsant activity of α‐Cl‐TMCD and α‐Br‐TMCD in rats and mice were reported in our previous publication (Pessah et al., 2009). In the current study, further quantification of α‐Cl‐TMCD anticonvulsant activity was performed in the mice MES, scMet, and 6‐Hz psychomotor seizure tests.…”

“…In the kindled rat model, α‐F‐TMCD exhibited excellent potency with an ED 50 value of 30 mg/kg. (Pessah et al., 2009). Further evaluation of the ability of α‐F‐TMCD to reduce the behavioral seizure score (BSS) in this model is reported here: α‐F‐TMCD decreased the behavioral seizure score [mean ± standard deviation (SD)] from 4.3 ± 0.7 to 0.8 ± 0.3 (15 min after dosing), and from 5.0 ± 0.7 to 1–1.8 (45–135 min after dosing) when the dose was increased from 11 to 89 mg/kg as depicted in Table 2.…”

“…α‐F‐TMCD and α‐Cl‐TMCD were synthesized according to previously described procedures (Pessah et al., 2009).…”

“…1) was the most potent, followed by α‐chlorine‐TMCD (α‐Cl‐TMCD, 7 , Fig. 1), whereas α‐bromo‐TMCD was inactive (Pessah et al., 2009). The rat scMet‐ED 50 of 6.4 mg/kg for α‐F‐TMCD shows that it is the most potent anticonvulsant compound among the hundreds of VPA analogs and derivatives that have been tested (Sobol et al., 2004; Shimshoni et al., 2008; Pessah et al., 2009).…”

Synthesis and Anticonvulsant Activity of N‐(Substituted)‐1‐methyl‐2,4‐dioxo‐1,2‐dihydroquinazoline‐3(4H)‐carboxamides

“…Epilepsy is a chronic disorder of the brain characterized by recurrent unprovoked seizures that affects about 1% of the world's population [1,2]. Despite the availability of many antiepileptic drugs (AEDs), there is still an urgent need for the development of more effective and safer AEDs, as about 30% of epileptic patients are not seizure-free with the existing AEDs [3,4].…”