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

• Published in: Bioorganic & medicinal chemistry 2006-02, Vol.14 (3), p.776-792
• Main Authors: Takano, Yasuo, Shiga, Futoshi, Asano, Jun, Hori, Wataru, Fukuchi, Kazunori, Anraku, Tsuyoshi, Uno, Takashi
• Format: Article
• Language: English
• Subjects: 3-Oxoquinoxaline-2-carboxylic acid; Animals; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral ischemia; Chemical Phenomena; Chemistry, Physical; Competitive AMPA receptor antagonist; Drug Design; Drug Stability; Evoked Potentials - drug effects; Excitatory amino acid; In Vitro Techniques; Male; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, AMPA - antagonists & inhibitors; Solubility
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.08.060

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