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-(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 = 6nM) 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.
Jimonet
P
P
Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Bohme
G A
GA
Bouquerel
J
J
Boireau
A
A
Damour
D
D
Debono
M W
MW
Genevois-Borella
A
A
Hardy
J C
JC
Hubert
P
P
Manfré
F
F
Nemecek
P
P
Pratt
J
J
Randle
J C
JC
Ribeill
Y
Y
Stutzmann
J M
JM
Vuilhorgne
M
M
Mignani
S
S
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009865:Oocytes / Q000187:drug effects; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
C425224:9-carboxymethyl-4-oxo-imidazo(1,2-a)indeno-(1,2-e)pyrazin-2-carboxylic acid; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D011719:Pyrazines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011718:Pyrazinamide; C005296:pyrazinoic acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid