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

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-(1 H-tetrazol-5 -ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosph onic acid 4i exhibited a strong and a selective binding affinity for the AM PA receptor (IC50 = 13 nM) and demonstrated potent antagonist activity (IC5 0 = 6 nM) at the ionotropic AMPA receptor. This compound also displayed goo d anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furtherm ore, a strong increase in potency was observed when given iv 3 h before tes t (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. (C) 2001 Elsevier Science Ltd. All rights reserved.