M. Schynts

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

The pharmacology of lipophilic 4-arylamino- and 4-cycloalkylaminopyrid-3-ylsulfonyl(thio)ureas and their synthesis designed from torasemide are described. These compounds could lead to a method of inhibiting the astrocytic Na+ 2C1− K+ cotransporter and thus treating cerebral edema. Their lipophilicity and ionization constants were determined. Seven lipophilic compounds (17, 18, 22, 23, 24, 32 and 36) exhibited a high inhibitory potency (IC50 < 10 μM) and had lost the diuretic properties of torasemide. One of them, N-{[4-(cycloheptylamino)pyrid-3-yl[sulfonyl}-N′-cycloheptylurea 17 (0.1-1 mg/kg) was found to increase the gasp delay in hypoxia-exposed mice. In preliminary experiments, 17 (1–2.5 mg/kg) strongly reduced the morbidity and mortality rate of gerbils after permanent left carotid artery ligation. In vitro experiments confirmed its antiedematous activity.

Na+,2Cl-,K+ cotransport system as a marker of antihypertensive activity of new torasemide derivatives

A series of compounds related to torasemide, a loop diuretic, were synthesized and examined for their diuretic potency and inhibitory activity on the erythrocyte and renal medullary thick ascending limb vesicle Na+,2Cl-,K+ cotransport in Milan hypertensive (MHS) and normotensive (MNS) rat strains, where previous studies had demonstrated an alteration of the cotransport system genetically related to hypertension. From the results of the screening, structure-activity relationships were drawn and two compounds, JDL 961 and C 2921 were selected. Their IC50 on renal vesicle cotransport were similar in the two strains (JDL 961: MHS = 1.8 microM; MNS = 1.2 microM; C 2921: MHS = 4 microM; MNS = 3.8 microM), and were 4-8 times lower than those of torasemide (MHS = 13 microM; MNS = 31 microM, P less than 0.01) and 50-60 times lower than those of bumetanide (MHS = 145 microM; MNS = 206 microM, P less than 0.05) taken as reference compounds. Their ability to reduce the development rate of hypertension was tested both in MHS and in Okamoto spontaneously hypertensive rats (SHR) strain, in which cotransport alterations are opposite to those of MHS. Both torasemide derivatives (7.5 mg.kg-1 os per day) prevented development of hypertension in the two strains. The time course of this hypotensive activity was faster and the percentage of blood pressure fall greater in MHS (20-25%) than in SHR rats (12-15%), even though the absolute value of blood pressure fall was similar in MHS (JDL 961 = -17 mm Hg; C 2921 = -30 mm Hg) and SHR (JDL 961 = -25 mm Hg; C 2921 = -20 mm Hg). A superimposable effect of bumetanide was observed in the two strains, but at 8 times higher daily dose (60 mg.kg-1). These results suggest that new loop diuretics can be selected for their antihypertensive activity on the basis of their in vitro potency in inhibiting the Na+,2Cl-,K+.

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

Abstract— A series of sulphonylthioureas related to torasemide, a high ceiling loop diuretic, were synthesized and found to inhibit the Na+ 2Cl− K+ co‐transporter of the thick ascending limb of the loop of Henlé. Their diuretic properties were studied (30 mg kg−1) after oral administration to rats. Lipophilic derivatives, very active in‐vitro, were found inactive orally and intraperitoneally in rats. The four most active compounds were examined for their dose‐dependent diuresis. Three of them showed a potency, water and electrolyte excretion similar to torasemide. The fourth molecule, a sulphonylthiourea (BM 20), exhibited relative potassium‐sparing properties and a minimal diuretic dose of 0·001 mg kg−1, 200 times lower than torasemide.

Synthèse, étude théorique et évaluation biologique de dérivés du 4-amino-4H-1,2,4-triazole analogues des antibiotiques β-lactamiques

Abstract The synthesis of three classes of potential antibiotic compounds derived from 4-amino-4H-1,2,4-triazole and related to β-lactam antibiotics is described. Their originality belongs to the replacement of the β-lactam carbonyl moiety by another electrophilic centre of the same sp 2 geometry. As a result, their interaction with the bacterial target enzyme might lead to the formation of a covalent complex different from the classical acylenzyme. A theoretical study of their structural analogy and their reactivity compared to those of a model β-lactam justifies their interest in the present context. However, the actual biological results indicate a lack of antibacterial activity.

Evaluation of the Inhibitory Activity on Serine and Aspartic Proteases of 4-Amino-4H-1,2,4-triazole and 5-Aminothiazole Derivatives Structurally Related to β-Lactam Antibiotics

Abstract— Twenty new derivatives of 4‐amino‐4H‐1,2,4‐triazole and 5‐aminothiazole have been examined for their inhibitory potential towards serine and aspartic proteases. Upon prolonged incubation with enzyme, the phenylacetylaminothiazolium salts exhibit progressive, time‐dependent inhibition of chymotrypsin according to a first‐order process. The formation of a tetrahedral transition state‐like complex by attack of the active‐site serine at the C2‐position of the pseudobase form of the thiazolium may be responsible for the observed effect. Triazolium salts appeared to be simple competitive inhibitors of this enzyme, effective in the Mm range concentration. Poor inhibitions of trypsin and pepsin were also obtained in the triazolium series. In spite of their structural analogy with β‐lactams, the selected derivatives failed to inhibit human leucocyte elastase.