Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.
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.
Cordi
Alex A
AA
Institut de Recherches Servier, Suresnes, France. alex.cordi@fr.netgrs.com
Desos
Patrice
P
Ruano
Elisabeth
E
Al-Badri
Hashim
H
Fugier
Claude
C
Chapman
Astrid G
AG
Meldrum
Brian S
BS
Thomas
Jean-Yves
JY
Roger
Anita
A
Lestage
Pierre
P
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*
D000927:Anticonvulsants; D063065:Organophosphonates; D015363:Quinolones; D013449:Sulfonamides; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid