title: Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl group and improved its good physicochemical properties by introduced CF3 group.
abstract: 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.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, Nogi-machi 2399-1, Simotsuga-gun, Tochigi 329-0114, Japan. yasuo.takano@mb.kyorin-pharm.co.jp
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takano
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shiga
authors.forename: Jun
authors.initials: J
authors.lastname: Asano
authors.forename: Wataru
authors.initials: W
authors.lastname: Hori
authors.forename: Tsuyosi
authors.initials: T
authors.lastname: Anraku
authors.forename: Takashi
authors.initials: T
authors.lastname: Uno
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; C498371:KRP 199; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA