Design and synthesis of novel 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group as superior AMPA receptor antagonists with good physicochemical properties.
We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h (KRP-199), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, 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, including stability to light and good solubility in aqueous solutions.
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
Hori
Wataru
W
Fukuchi
Kazunori
K
Anraku
Tsuyoshi
T
Uno
Takashi
T
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D004355:Drug Stability; D005071:Evoked Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012995:Solubility
D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA