benzofurans and zileuton

SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzo furanyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds. Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH > 5 and different degradative pathways at pH < 5. The pathway at pH > 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH < 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.

Topics: Benzofurans; Drug Stability; Hydrogen-Ion Concentration; Hydroxyurea; Kinetics; Lipoxygenase Inhibitors; Urea; Water

Prostaglandins and leukotrienes differentially regulate the production of interleukin-1 (IL-1) in monocytes. It was, therefore, decided to investigate the effects of some 5-lipoxygenase inhibitors compared with standard IL-1 synthesis inhibitors on the production of IL-1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1-5 days. Total bioactive IL-1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D-10 T-cell bioassay. Some assays of interleukins 1 alpha, 1 beta, 6 or 8 were performed by ELISA. Of the 5-lipoxygenase inhibitors investigated, MK-886(3-(1-(4-chlorobenzyl)-3-tert-butyl-thio-5-isopropylindol-2- yl)-2,2 -dimethyl propanoic acid), L-656,224 ((7-chloro-2-[4-methoxypenyl]methyl)-3 -methyl-5-propyl-4-benzofuranol), PF-5901 and tepoxalin were the most potent inhibitors of IL-1 production. While the PF-5901 was effective at 5-30 microM and tepoxalin was effective at 1-10 microM, the others were the most potent having minimal inhibitory activity in the range of 0.01-0.1 microM. The presumed IL-1-synthesis inhibitors, tenidap and IX-207,887, were inactive at concentrations of 30-50 microM. Leukotriene B4 (1-100 ng/mL-1) added to MK-886 (5 microM)-treated cultures reversed the inhibitory effects of the latter on IL-1, confirming the role of 5-lipoxygenase products in the regulation of IL-1 production. Addition of polyethylene glycol 8000 to MI-886-treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL-1 inhibitors. MK-886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL-6 and IL-8. The results suggest that some 5-lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.

Topics: Animals; Benzofurans; Enzyme-Linked Immunosorbent Assay; Hip Joint; Humans; Hydroxyurea; Indoles; Interleukin-1; Knee Joint; Lipoxygenase Inhibitors; Naphthalenes; Organ Culture Techniques; Oxindoles; Pyrazoles; Quinolines; Structure-Activity Relationship; Swine; Synovial Membrane; Tarsus, Animal; Thiazoles; Thiophenes

Methoxyalkyl thiazoles have been identified as a novel series of selective 5-lipoxygenase inhibitors with anti-inflammatory properties (Bird et al., J Med Chem 34: 2176-2186, 1991). Based on their structure, it was proposed that the potency of these compounds is not due to redox or iron-chelating properties. In the studies reported here, it was found that the model compounds 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (ICI 211965) and 3-[1-(4-chlorobenzyl)-4-methyl-6-(5- phenylpyridin-2-ylmethoxy)-4,5-dihydro-1H-thiopyrano[2 ,3,4-c,d]indol-2- yl]-2,2-dimethylpropanoic acid (L-689,065) (1) are inactive as reducing substrates in the 5-lipoxygenase-catalyzed decomposition of lipid hydroperoxides, (2) inhibit the 5-lipoxygenase-catalyzed reaction of reducing agents with lipid hydroperoxides, and (3) strongly inhibit the turnover-dependent inactivation of 5-lipoxygenase. These three observations with ICI 211965 and L-689,065 are in contrast to the behavior of other potent 5-lipoxygenase inhibitors from other structural classes, such as L-670,630, BW A4C, and zileuton, which all function as reducing substrates for 5-lipoxygenase. The data indicate that methoxyalkyl thiazoles and thiopyranoindoles are reversible dead-end inhibitors of 5-lipoxygenase and that the effects of inhibitors on the pseudoperoxidase activity and rate of enzyme inactivation provide simple tests to distinguish between redox and non-redox inhibitors of 5-lipoxygenase.

Topics: Arachidonate 5-Lipoxygenase; Benzeneacetamides; Benzofurans; Enzyme Inhibitors; Humans; Hydroxamic Acids; Hydroxyurea; Indoles; Leukotrienes; Lipid Peroxides; Lipoxygenase Inhibitors; Naphthalenes; Oxidation-Reduction; Thiazoles