ABSTRACT
We describe the design, synthesis, and biological properties of a novel series of 7-substituted 6-nitro-3-oxoquinoxaline-2-carboxylic acids. After designing, studying the structure-activity relationships, and evaluating the properties of various compounds, we found that 7-heterocyclic-6-nitro-3-oxoquinoxaline-2-carboxylic acids that contain a substituted phenyl group linked through urethane at the 7 position possess good alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) antagonistic activity. Among the compounds tested, compound 29p (GRA-293), which has a 4-carboxy group on the terminal phenyl moiety, exhibited high potency and selectivity for the AMPA-R in vitro and good neuroprotective efficacy in vivo. It also showed good aqueous solubility.
Subject(s)
Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Nitro Compounds/chemical synthesis , Nitro Compounds/pharmacology , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Receptors, AMPA/antagonists & inhibitors , Animals , Brain Ischemia/prevention & control , Excitatory Amino Acid Antagonists/chemical synthesis , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Radioligand Assay , Rats , Rats, WistarABSTRACT
We describe the synthesis, physicochemical, and biological properties of a novel series of 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acids with a substituted phenyl group attached through a urethane linkage at the C-7 position. We found that the introduction of trifluoromethyl group at the C-6 position brought about good biological activity and physicochemical properties. Among them, compound 9k (KRP-199), which has a 4-carboxyphenyl group, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties such as stability to light and good solubility in aqueous solutions.
Subject(s)
Imidazoles/chemical synthesis , Neuroprotective Agents/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, AMPA/antagonists & inhibitors , Animals , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Disease Models, Animal , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Infusions, Intravenous , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
The synthesis and biological properties of a novel class of 7-heterocycle-substituted quinoxalinecarboxylic acids, which bear a substituted phenyl group through a urethane linkage at the C-7 position, are described. One of the synthesized compounds, 15l, which has a 4-carboxyphenyl carbamoyloxymethyl imidazole group at the C-7 position and is water-soluble, was found to possess high potency in vitro and showed excellent neuroprotective efficacy in vivo.
