Design, synthesis, and AMPA receptor antagonistic activity of a novel 6-nitro-3-oxoquinoxaline-2-carboxylic acid with a substituted phenyl group at the 7 position

• Published in: Bioorganic & medicinal chemistry 2005-10, Vol.13 (20), p.5841-5863
• Main Authors: Takano, Yasuo, Shiga, Futoshi, Asano, Jun, Ando, Naoki, Uchiki, Hideharu, Fukuchi, Kazunori, Anraku, Tsuyosi
• Format: Article
• Language: English
• Subjects: 3-Oxoquinoxaline-2-carboxylic acid; Animals; Biological and medical sciences; Brain Ischemia - prevention & control; Cerebral ischemia; Competitive AMPA-R antagonist; Excitatory amino acid; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Medical sciences; Models, Molecular; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Nitro Compounds - chemical synthesis; Nitro Compounds - pharmacology; Pharmacology. Drug treatments; Quinoxalines - chemical synthesis; Quinoxalines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, AMPA - antagonists & inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.05.030

We describe the design, synthesis, and biological properties of a novel series of 6-nitro-3-oxoquinoxaline-2-carboxylic acids which bear a substituted phenyl group through a urethane linkage at the 7 position. 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 α-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.