Synthesis and pharmacology of pyrid-3-ylsulfonylcyanoguanidines as diuretic

Masereel, Bernard; Dupont, L.; Laeckmann, Didier; Liégeois, JF; Pirotte, Bernard; Tullio, Pascal De; Delarge, J.

doi:10.1016/0223-5234(96)88244-4

Cited by 14 publications

(25 citation statements)

References 20 publications

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“…Despite possessing chemical structures very similar to those of diuretics such as torasemide, BM-20 (Masereel et al 1993) and BM-106 (Masereel et al 1995), BM-144 and BM-500 failed to increase the volume of urine excreted by the rat in the 4 h after oral or intraperitoneal administration of 30 mg kg À1 (Table 4). It is of structural interest to note that some hypoglycaemic sulphonylureas have been reported to block the aorta contractions induced by U-46619 (Delaey & Van de Voorde 1995).…”

Section: Resultsmentioning

confidence: 99%

“…Torasemide and its derivatives were synthesized according to general synthetic pathways previously reported (Masereel et al 1994(Masereel et al , 1995. Their elemental analyses for C, H, N and S were performed with a Carlo-Erba (Milano, Italy) analyser and were within 0Á4% of the theoretical values.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

“…This drug is a loop-diuretic with a sulphonylurea function which acts by inhibiting the Na a2Cl À aK cotransporter located on the luminal membrane of Henle's loop (Friedel & Buckley 1991). Several molecules structurally related to torasemide have been described for their diuretic (Masereel et al 1993(Masereel et al , 1995, antihypertensive (Masereel et al 1992), neuroprotective (Masereel et al 1994) or anticonvulsive (Masereel et al 1997(Masereel et al , 1998 properties. With the aim of discovering potent and selective TXA 2 antagonists we have investigated the TXA 2 antagonism of N-cyano-N H -{[4-(3 Hmethylphenylamino) pyrid -3 -yl]sulphonyl}homopiperidinoamidine (BM-144) and N-isopropyl-N H -[5-nitro-2-(3 H -methylphenylamino)benzenesulphonyl]urea (BM-500), structurally related to torasemide ( Figure 1).…”

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confidence: 99%

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Thromboxane A2 Receptor Antagonism in Man and Rat by a Sulphonylcyanoguanidine (BM-144) and a Sulphonylurea (BM-500)

Masereel

Damas

Fontaine

et al. 1999

Journal of Pharmacy and Pharmacology

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Torasemide, a loop diuretic, has been reported to relax dog coronary artery precontracted by thromboxane A2 (TXA2), an endogenous prostanoid involved in cardiovascular and pulmonary diseases. N-cyano-N'-[[4-(3'-methylphenylamino)pyrid-3-yl]sulphonyl] homopiperidinoamidine (BM-144) and N-isopropyl-N'-[5-nitro-2-(3'-methylphenylamino)-benzenesulphon yl]urea (BM-500), chemically related to torasemide, have been examined for their TXA2 antagonism. The affinity (IC50, the concentration resulting in 50% inhibition) of BM-144 and BM-500 for the TXA2 receptor of washed platelets from man was 0.28 and 0.079 microM, respectively. This is better than for sulotroban (IC50 = 0.93 microM) but less than for SQ-29548 (IC50 = 0.021 microM), two TXA2 antagonists used as reference. The aggregation of platelets from man induced by arachidonic acid was prevented by BM-144 (IC50 = 9.0 microM) and by BM-500 (IC50 = 14.2 microM). Similar results were obtained by use of U-46619, a TXA agonist, as aggregating agent (BM-144, IC50 = 12.9 microM and BM-500, IC50 = 9.9 microM). The contracting effect of U-46619 on rat stomach strip was abolished by BM-144 (IC50 = 1.01 microM) and BM-500 (IC50 = 2.54 microM). Both drugs (BM-144: IC50 = 0.12 microM and BM-500: IC50 = 0.19 microM) also relaxed rat aorta precontracted by U-46619; both were more potent than sulotroban (IC50 = 1.62 microM). The two torasemide derivatives (100 microM) did not significantly affect the myo-stimulating effect of some prostaglandins (PGE2, PGI2, PGF2alpha) or aorta contraction elicited by KCl (30 mM). They did not modify 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 TXA2 receptor antagonists and offer a novel template for the design of more potent molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Drugs and Chemicalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Thromboxane A2 Receptor Antagonism in Man and Rat by a Sulphonylcyanoguanidine (BM-144) and a Sulphonylurea (BM-500)

Masereel

Damas

Fontaine

et al. 1999

Journal of Pharmacy and Pharmacology

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“…Torasemide and its pyridinic derivatives were synthesized by general synthetic pathways described elsewhere (Delarge et al 1980(Delarge et al , 1981Masereel et al 1992Masereel et al , 1993Masereel et al , 1994Masereel et al , 1995. Sodium arachidonate (Sigma, Belgium) was diluted with 0Á9% aqueous NaCl.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

“…The observation that torasemide, a sulphonylurea with strong ceiling diuretic properties, induced concentration-dependent relaxation of the canine coronary artery precontracted with TxA 2 (Uchida et al 1992) led to the investigation as potential TxA 2 receptor agonists of a series of pyridinic sulphonylureas, sulphonylthioureas and sulphonylcyanoguanidine derivatives previously studied as Na =K =2Cl À cotransporter inhibitors (Delarge et al 1980(Delarge et al , 1981Masereel et al 1992Masereel et al , 1993Masereel et al , 1994Masereel et al , 1995. Their af®nity for TxA 2 =PGH 2 receptors was determined by their tendency to displace [ 3 H]SQ-29548, a competitive TxA 2 receptor agonist, from its site on washed platelets from man.…”

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Pharmacomodulation Studies of Torasemide Leading to Original Non-carboxylic Thromboxane A<SUB>2</SUB> Receptor Antagonists

Dogné

Leval

Neven

et al. 2000

Pharmacy and Pharmacology Communications

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Because torasemide, a loop diuretic, dose‐dependently relaxes canine coronary artery precontracted with thromboxane A2 (TxA2), a series of pyridine derivatives have been investigated with the aim of developing original TxA2 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 TxA2 receptor of washed platelets from man were 161, 1. 75 and 0.54 μM, respectively. The IC50 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 TxA2 (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 (IC50 11.5 μM) when U‐46619, a stable TxA2 agonist, was used as the aggregating agent. This molecule can be regarded as a template for the design of novel non‐carboxylic TxA2 receptor antagonists.

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