Design, synthesis and biological activity of a series of torasemide derivatives, potent blockers of the Na+ 2Cl- K+ co-transporter: in-vitro study.
Pharmacomodulation of the torasemide molecule, a loop diuretic inhibiting Na+ 2Cl- K+ co-transport in the thick ascending limb of the loop of Henlé has been performed in order to obtain new long-acting diuretics. The aim of this study was to decrease the metabolism of the drug and to slow down its rate of excretion by increasing its hydrophobicity. The present study describes the synthesis and the inhibitory potency of new torasemide derivatives in the bioassay system of the cortical thick ascending limb of rabbit. A correlation between the lipophilicity (log P') of these substances and their activity as inhibitors of the Na+ Cl- K+ co-transporter was observed. The present design led to compounds more active than torasemide. Structure-activity relationships permit us to propose an interaction model between torasemide derivatives and the Na+ 2Cl- K+ co-transport system of the cortical thick ascending limb.
Department of Medicinal Chemistry, University of Liege, Belgium.
B
B
Masereel
E
E
Lohrmann
M
M
Schynts
B
B
Pirotte
R
R
Greger
J
J
Delarge
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004232:Diuretics / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000378:metabolism; D066298:In Vitro Techniques; D008138:Loop of Henle / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D000077786:Torsemide
D004232:Diuretics; D004573:Electrolytes; D013449:Sulfonamides; D000077786:Torsemide