Thromboxane A(2) receptor antagonism in man and rat by a sulphonylcyanoguanidine (BM-144) and a sulphonylurea (BM-500)

Torasemide, a loop diuretic, has been reported to relax dog coronary artery precontracted by thromboxane A(2) (TXA(2)), an endogenous prostanoid invol ved in cardiovascular and pulmonary diseases. N-cyano-N'-{[4-(3'-methylphen ylamino)pyrid-3-yl]sulphonyl)homopiperidinoamidine (BM-144) and N-isopropyl -N'-[5-nitro-2-(3'-methylphenylamino)benzenesulphonyl]urea (BM-500), chemic ally related to torasemide, have been examined for their TXA(2) antagonism. The affinity (IC50, the concentration resulting in 50% inhibition) of BM-14 4 and BM-500 for the TXA(2) receptor of washed platelets from man was 0.28 and 0.079 mu M, respectively. This is better than for sulotroban (IC50 = 0. 93 mu M) but less than for SQ-29548 (IC50 = 0.021 mu M), two TXA(2) antagon ists used as reference. The aggregation of platelets from man induced by ar achidonic acid was prevented by BM-144 (IC50 = 9.0 mu M) and by BM-500 (IC5 0 = 14.2 mu M). Similar results were obtained by use of U-46619, a TXA agon ist, as aggregating agent (BM-144, IC50 = 12.9 mu M and BM-500, IC50 = 9.9 mu M). The contracting effect of U-46619 on rat stomach strip was abolished by BM-144 (IC50 = 1.01 mu M) and BM-500 (IC50 = 2.54 mu M). Both drugs (BM -144: IC50 = 0.12 mu M and BM-500: IC50 = 0.19 mu M) also relaxed rat aorta precontracted by U-46619; both were more potent than sulotroban (IC50 = 1. 62 mu M). The two torasemide derivatives (100 mu M) did not significantly a ffect the myo-stimulating effect of some prostaglandins (PGE(2), PGI(2), PG F(2 alpha)) or aorta contraction elicited by KCl (30 mM). They did not modi fy rat diuresis after administration of a 30-mg kg(-1) dose. In conclusion, BM-144 and BM-500 can be regarded as novel non-carboxylic TX A(2) receptor antagonists and offer a novel template for the design of more potent molecules.