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.
Bioorganic & medicinal chemistry 2005 Oct 15; 13(20):5841-63
Takano Y Y, Shiga F F, Asano J J, Ando N N, Uchiki H H, Fukuchi K K, Anraku T T
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Simotsuga-gun, Tochigi 329-0114, Japan. yasuo.takano@mb.kyorin-pharm.co.jp
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.