Pharmacomodulation studies of torasemide leading to original non- carboxylic thromboxane A receptor antagonists

Because torasemide, a loop diuretic, dose-dependently relaxes canine coronary artery precontracted with thromboxane A (TxA), a series of pyridine derivatives have been investigated with the aim of developing original TxA receptor antagonists. A binding test showed the affinity (IC50; the dose reducing binding by 50%) of one sulphonylurea derivative (BM 27) and two sulphonylcyanoguanidine derivatives (BM 114 and BM 115) for the TxA receptor of washed platelets from man were 1.61, 1.75 and 0.54 μM, respectively. The IC of torasemide was only 2.69 μM. Their antagonism was confirmed by the capacity of the compounds to prevent the aggregation of platelets, from man, induced by arachidonic acid, the biological precursor of TxA (IC50: BM 114, 29.3 μM; BM 115, 12.0 μM; BM 27, 234 μM; torasemide, 350 μM; sulotroban, 12.3 μM). Similar results were obtained with the best compound BM 115 (IC 11.5 μM) when U-46619, a stable TxA agonist, was used as the aggregating agent. This molecule can be regarded as a template for the design of novel non-carboxylic TxA receptor antagonists.