Design, Synthesis and Biological Activity of a Series of Torasemide Derivatives, Potent Blockers of the Na+ 2Cl− K+ Co-transporter: In-vitro Study

Abstract

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.

Torasemide Derivatives: New Perspectives

“…Their lipophilicity (log P') was determined and expressed as the logarithm of the partition coefficient in n-octanol/pH 7.4 phosphate buffer. Log P' of torasemide was found to be +0.45 (54). Furosemide (-0.92) and bumetanide (-0.30) are more hydrophilic (54).…”

“…Synthesis of torasemide and its derivatives was previously described (16,17,20,21,54,55,57,75). Their lipophilicity (log P') was determined and expressed as the logarithm of the partition coefficient in n-octanol/pH 7.4 phosphate buffer.…”

“…In this article, the cellular mechanism, pharmacology and therapeutic potential of torasemide derivatives will be reviewed. found to be +0.45 (54). Furosemide (-0.92) and bumetanide (-0.30) are more hydrophilic (54).…”

“…found to be +0.45 (54). Furosemide (-0.92) and bumetanide (-0.30) are more hydrophilic (54). The pKa for the sulphonylurea moiety of torasemide is 6.68.…”

A Sulphonylthiourea (BM 20) Related to Torasemide: a new Loop Diuretic with Relative Potassium-sparing Properties

“…To test the hypothesis of poor oral absorption, intravenous testing would be appropriate. However, the hydrophobic sulphonylureas (BM 6, BM 9 and BM 27), which were very active in-vitro (Masereel et al 1992) were so poorly soluble, even as sodium salts or with a co-solvent, that the intraperitoneal route was preferred ( Table 4). The mode of administration did not modify the urine excretion induced by torasemide.…”