S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase.

microdant stress is involved in the events that accompany endothelial cell expression of adhesion molecules and leukocyte adherence in many disease states, including atherosclerosis. A recently discovered benzo(b)pyran-4-one derivative, S17834 (10 to 50 micromol/L), reduced tumor necrosis factor-stimulated vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell adhesion molecule-1 and E-selectin were also inhibited by S17834, but platelet endothelial cell adhesion molecule-1 was not. Adherence of U937 monocytic cells to the endothelial cells as well as to plastic plates coated with soluble VCAM, intercellular cell adhesion molecule-1, P-selectin, and E-selectin was also decreased. Consistent with an antioxidant mechanism of action, S17834 (10 to 50 micromol/L) inhibited tumor necrosis factor-stimulated release of superoxide from endothelial cells measured by cytochrome c reduction. S17834 had no effect on superoxide produced by xanthine oxidase, indicating that rather than by acting as a scavenger of superoxide anion, the drug acts by inhibiting the production of free radicals. Indeed, S17834 inhibited NADPH oxidase activity of endothelial cell membranes. The ability to inhibit superoxide anion production appears to be key in the effect of S17834 on superoxide anion production and VCAM expression, because these actions were mimicked by adenovirus-mediated overexpression of superoxide dismutase. Furthermore, these actions may be relevant in vivo, because S17834 reduced aortic superoxide anion levels by 40% and aortic atherosclerotic lesions by 60% in apolipoprotein E-deficient mice. These results indicate that S17834 inhibits adhesion molecule expression and adherence of leukocytes to endothelial cells as well as aortic atherogenesis and that perhaps these effects can be explained by its ability to inhibit endogenous superoxide anion production.

Preparation and pharmacological profile of 2-trifluoromethyl-benzo(8,9)-1,3-diaza-spiro (4,6)-undeca-2,8-diene and its enantiomers as new anti-obesity agents.

Obesity affects a large population of industrialised countries in which occurrence may reach 20%. The multifactorial aspect of the pathology prompted us to develop new entities associating favourable effects on both eating behaviour and metabolic parameters. The 2-trifluoromethyl-benzocyloheptene moiety has been combined with an imidazoline ring for synthesising a new anti-obesity agent. Preparation of the already known 2-trifluoromethyl-5-H-6,7,8,9-tetrahydro-benzocyclohepten-7-one as a key intermediate has been significantly improved, and an enantioselective procedure has been developed for imidazoline construction. The syntheses and pharmacological profiles of the compounds are presented here, particularly the effects on eating behaviour and body weight, and the putative involvement of the L-enantiomer in the treatment of metabolic diseases.

Amino derivatives of phenyl alkyl thiophene as inhibitors of bone resorption. Structure-activity relationship.

Metabolism of arachidonic acid through the 5-lipoxygenase (LO) pathway generates compounds that stimulate osteoclastic bone resorption; since LO metabolites might play a role in bone loss due to excessive resorption it was tried to develop a series of antiresorptive agents starting from an already known LO inhibitor. Of the 35 compounds synthesized, 11 strongly inhibited (10 mumol/l) retinoic acid-induced bone resorption in cultured mouse calvariae; they were also tested for their effect on LO activity using rat peritoneal neutrophils, but no correlation could be drawn between inhibition of LO and bone resorption. Other pathways, still to be identified, must therefore be targeted by these compounds even though LO inhibition might contribute to their effects on bone. Two compounds selected for further studies were found active on parathyroid hormone-induced osteolysis, while they had no effect on basal resorption; they must, therefore, act at some key point in the process of activation of osteoclastic resorption. This series of compounds may represent a new way for the treatment of bone loss due to excessive resorption.