B. Masereel

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo.

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week−1 with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

New Developments on Thromboxane and Prostacyclin Modulators Part I: Thromboxane Modulators

The pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases can be related to arachidonic acid (AA) metabolites. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2)(PGH(2)), which results from the enzymatic degradation of AA by the cyclooxygenases. TXA(2) is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction. It is involved in a series of major pathophysiological states such as asthma, myocardial ischemia, pulmonary hypertension, and thromboembolic disorders. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by several pharmaceutical companies since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. Moreover, the recent literature reported the interest of thromboxane modulators, which combine another pharmacological activity such as, platelet activating factor antagonism, angiotensin II antagonism, or 5-lipoxygenase inhibition. In this review, we will propose a description of the recently described thromboxane modulators of major interest from both a pharmacological and a chemical point of view.

Pharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Effects of BM-567 on osteogenic sarcoma-cell-induced platelet aggregation

Evidence exists that a large number of tumor cells such as osteosarcoma cells stimulate platelet aggregation, which can be an early step in the metastatic processes of these tumors. Thromboxane A(2) (TXA(2)) is released during platelet aggregation, and it has been suggested that this release may be pathogenic for tumor metastasis for several reasons:Some tumors release large amounts of TXA(2) compared to normal tissue.TXA(2) potentiates tumor growth in culture and increases metastasis in animals.TXA(2) is a potent stimulant of platelet aggregation and causes vascular injuries that may promote implantation of tumor cell-platelet aggregates. If TXA(2) participates in tumor metastasis, it may be hypothesized that TXA(2) inhibitors should decrease tumor metastasis. So, we have evaluated the effects of the original TXA(2) synthase inhibitor and TXA(2) receptor antagonist BM-567 on platelet aggregation induced by osteosarcoma cells using MG-63 tumor cells. Results obtained showed that this drug inhibited both MG-63 tumor-cell-induced platelet aggregation and platelet TXA(2) release following the tumor cell stimulation with IC(50) values of 3.04x10(-7) and 2.51x10(-8)M, respectively.

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

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 (ED50) 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.

Effects of U-46619 on Pulmonary Hemodynamics Before and After Administration of BM-573, a Novel Thromboxane A2 Inhibitor

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A2 (TXA 2) agonist, before and after administration of a novel TXA 2 receptor antagonist and synthase inhibitor (BM-573). Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10min before each U-46619 injection. Consecutive changes in pulmonary hemodynamics, including characteristic resistance, vascular compliance, and peripheral vascular resistance, were continuously assessed during the experimental protocol using a four-element Windkessel model. At 2 mg/kg, BM-573 completely blocked pulmonary hypertensive effects of U-46619 but pulmonary vascular compliance still decreased. This residual effect can probably be explained by a persistent increase in the tonus of the pulmonary vascular wall smooth muscles sufficient to decrease vascular compliance but not vessel lumen diameter. Such molecule could be a promising therapeutic approach in TXA 2 mediated pulmonary hypertension as it is the case in pulmonary embolism, hyperacute lung rejection and endotoxinic shock.

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.

Effects of Bm-573, a Novel Thromboxane A2 Inhibitor, on Pulmonary Hemodynamics in Endotoxic Shock

Thromboxane A 2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The effects of a novel dual TXA 2 synthase inhibitor and TXA 2 receptor antagonist (BM-573) on pulmonary hemodynamics were investigated in endotoxic shock. 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 ± 1.8 (T0) to 42 ± 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 ± 1.6 (T0) to 25 ± 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO 2 decreased from 131 ± 21 (T0) to 74 ± 12 mmHg (T300) (p < 0.05), while in Anta group, PaO 2 was 241 ± 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA 2 plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA 2 synthesis and of TXA 2 receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation.

N2-Cyano-N1-isopropyl-N3-[4-(3-methylphenylamino)-3-pyridylsulfonyl]guanidine

The title compound, C 17 H 20 N 6 O 2 S, is a bioisoster of torasemide, a loop diuretic whose structure has been described previously. The sulfonylurea chain of torasemide is replaced by a sulfonylcyanoguanidine function. Whereas the torasemide molecule and some sulfonylurea derivatives exhibit one of the three α, β or γ conformations, the conformation being assigned according to the torsion angles in the side chain, the title compound displays a new δ conformation. This conformation is stabilized by two intramolecular N-H...O hydrogen bonds. A prototropic form of the title compound corresponding to a zwitterion [-S-N - -C-, N + -H (pyridinium)] is observed {i.e N 2 -cyano-N 1 -isopropyl-N 3 -[4-(3-methylphenylamino)-3-pyridiniosulfonyl]guanidin-3-ide}. The crystal cohesion is the result of both van der Waals interactions and one intermolecular N + -H...N - hydrogen bond involving the N atoms of the zwitterion

3-Methyl-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide

The title compound, C7H7N302S, was prepared for comparison with diazoxide, an antihypertensive agent, from a structural and pharmacological point of view. The crystal structure determination shows that the 4H (rather than 2H) tautomeric form is preferentially adopted by this pyridothiadiazine derivative in the solid state.

2,4,7-Trimethyl-2,3-dihydro-4H-pyrido[4,3-e]-1,2,4-thiadiazinium 1,1-dioxide iodide

The title compound, C 9 H 14 N 3 O 2 S + .I - , is a new drug developed as a structural derivative of the antihypertensive agent diazoxide. The C atom at the 3 position is sp 3 hybridized, whereas in the related compounds for which the structures have been determined so far it is sp 2 hybridized. The distances and angles around the N atom in the aromatic ring are consistent with a pyridinium cationic moiety.