Synthesis and pharmacology of pyrid-3-yl sulfonylureas and thioureas as astrocytic Na+ 2C1− K+ cotransporter inhibitors

Masereel, Bernard; Renard, Pierre; Schynts, M.; Pirotte, Bernard; Tullio, Pascal De; Delarge, J.

doi:10.1016/0223-5234(94)90145-7

Cited by 18 publications

(16 citation statements)

References 25 publications

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“…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: Drugs and Chemicalsmentioning

confidence: 99%

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confidence: 99%

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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“…Due to the nitrobenzene ring, the pK a value of the sulfonylurea 7 (3.90) was lower than that of torasemide (6.68), its pyridine counterpart (Masereel et al 1994). In the pyridine series, we demonstrated that the pK a of torasemide was higher than that of its sulfonylcyanoguanidine counterpart (pK a l 6.00) .…”

Section: Interaction With Arg 295mentioning

confidence: 74%

“…Extrapolated to 0 % of methanol, the pK a value of 7 was 3.90p0.01 (Figure 4). Compared with torasemide (5 ; pK a l 6.68) (Masereel et al 1994), the replacement of the pyridine by a nitrobenzene ring strongly dropped the pK a value of the sulfonylurea function. These results indicated clearly that 7 was under its anionic form at physiological pH (7.4) and was able to establish an ionic bond with the TXA 2 receptor.…”

Section: Dissociation Constants (Pk a )mentioning

confidence: 91%

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor

Dogné

Rolin

Michaux

et al. 2001

Journal of Pharmacy and Pharmacology

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The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.

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“…According to their anticonvulsant profile, neurotransmitters such as X-aminobutyric acid (GABA), glycine, and NMDA do not seem to be implicated in the mechanism of action. Recently, furosemide, which also blocks the renal and the astrocytic Na+ 2 HCI-K+ cotransporter (1,2), was suggested to play a crucial role in the synchronization of neural activity (4). The anticonvulsant properties of torasemide derivatives could perhaps be mediated by a similar pathway.…”

Section: Resultsmentioning

confidence: 99%

Anticonvulsant Activity of Pyrid‐3‐yl‐Sulfonyl Ureas and Thioureas

Masereel

Lambert²,

Dogné

et al. 1997

Epilepsia

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Summary:The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two stucturally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED,,) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest. Key Words: Sulfonylurea-Sulfonylthiourea-Epilepsy-Anticonvulsan-BM 34. N-[ (4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycbheptyl urea, called BM 27, (Table 1) is a sulfonylurea that exhibits neuroprotective properties against normobaric hypoxia in mice (0.1-1 mg/kg) and cerebral ischemia in gerbils (1-2.5 mg/kg) (1). It is structurally related to torasemide (a loop diuretic) acting, as does furosemide (2), by the inhibition of the Na+ 2 HC1-K+ cotransporter of the thick ascending limb of Henle's loop (3). The central properties of BM 27 probably can be attributed to its ability to inhibit the astrocytic Na+ 2 HC1-K+ cotransporter (1). As furosemide blocks kainic acid-induced electrical discharges recorded from cortex (4), and in view of the antiepileptic properties attributed to the neuroprotective agents such as the antagonists of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors (5-9), we investigated the anticonvulsant activity of BM 27 and some related substances. In this study, BM 27 and two sulphonylthioureas, BM 11 and BM 34, were selected to be tested in several classic anticonvulsant assays to define their pharmacologic profile. METHODS ChemistryAll compounds were synthesized as described previously (1). Their elemental analyses for C, H, N, and S were within 0.4% of the theoretic values. 'H-nuclear magnetic resonance (NMR) and IR spectra were in complete agreement with their chemical structure. LipophilicityThe lipophilicity of compounds (log P) was measured at pH 7.4 and expressed as the logarithm of their partition coefficient in the n-octanollphosphate buffer system. The log P of a series of standards chosen in a wide range of log P values (from +0.16 to +2.0) was determined by using the shake-flask method (10). As reported (1,l l), a reverse-phase high performance liquid chromatography system was used to determine their capacity factor (log k') which corresponds to log (~-t,)/t,)] where t, is the drug retention time and t, is the void volume. A calibration curve calculated from log P and log k' of standards was used to interpolate the log P of the studied compounds. Pharmacology Anticonvulsant activityAll compounds were administered to OF1 male mice (22-25 g; Iffa-Credo, Les Onci...

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Synthesis and pharmacology of pyrid-3-yl sulfonylureas and thioureas as astrocytic Na+ 2C1− K+ cotransporter inhibitors

Cited by 18 publications

References 25 publications

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

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

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor

Anticonvulsant Activity of Pyrid‐3‐yl‐Sulfonyl Ureas and Thioureas

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