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.
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.
Takano
Yasuo
Y
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
Shiga
Futoshi
F
Asano
Jun
J
Ando
Naoki
N
Uchiki
Hideharu
H
Fukuchi
Kazunori
K
Anraku
Tsuyosi
T
D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
C506353:6-nitro-3-oxoquinoxaline-2-carboxylic acid; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011810:Quinoxalines; D018091:Receptors, AMPA