title: Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.
abstract: We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.
authors.affiliation: Institut de Recherches Servier, Suresnes, France. alex.cordi@fr.netgrs.com
authors.forename: Alex A
authors.initials: AA
authors.lastname: Cordi
authors.forename: Patrice
authors.initials: P
authors.lastname: Desos
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ruano
authors.forename: Hashim
authors.initials: H
authors.lastname: Al-Badri
authors.forename: Claude
authors.initials: C
authors.lastname: Fugier
authors.forename: Astrid G
authors.initials: AG
authors.lastname: Chapman
authors.forename: Brian S
authors.initials: BS
authors.lastname: Meldrum
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Thomas
authors.forename: Anita
authors.initials: A
authors.lastname: Roger
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D008811:Mice, Inbred DBA; D009865:Oocytes / Q000187:drug effects; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014981:Xenopus / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
chemical_list: D000927:Anticonvulsants; D063065:Organophosphonates; D015363:Quinolones; D013449:Sulfonamides; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid