Title of article :
Bioisosteres of 9-Carboxymethyl-4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent In Vivo AMPA antagonists with longer durations of action
Author/Authors :
Patrick Jimonet، نويسنده , , Georg Andrees Bohme، نويسنده , , Jean Bouquerel، نويسنده , , Alain Boireau، نويسنده , , Dominique Damour، نويسنده , , Marc-Williams Debono، نويسنده , , Arielle Genevois-Borella، نويسنده , , Jean-Claude Hardy، نويسنده , , Philippe Hubert، نويسنده , , Franco Manfré، نويسنده , , Patrick Nemecek، نويسنده , , Jeremy Pratt، نويسنده , , John C. R. Randle، نويسنده , , Yves Ribeill، نويسنده , , Jean-Marie Stutzmann، نويسنده , , Marc Vuilhorgne، نويسنده , , Serge Mignani، نويسنده ,
Abstract :
A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a strong and a selective binding affinity for the AMPA receptor (IC50=13 nM) and demonstrated potent antagonist activity (IC50=6 nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furthermore, a strong increase in potency was observed when given iv 3 h before test (ED50=3.5 instead of 25.6 mg/kg for the corresponding 9-carboxymethyl-2-carboxylic acid analogue). These data confirmed that there is an advantage in replacing the classical carboxy substituents by their bioisosteres such as tetrazole or phosphonic acid groups.
