The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.

Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.

The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Basophil mediator release in atopic dermatitis.

Basophils have been implicated as a source of histamine and pro-inflammatory eicosanoids in atopic dermatitis. However, mechanisms regulating basophil mediator release are not understood. An H3 receptor involved in the control of histamine synthesis and release has been identified in nervous tissue. In this study we have investigated 1) release of histamine, leukotriene C4, and prostaglandin D2 from anti-immunoglobulin E (IgE)-stimulated basophils of adults with atopic dermatitis and unaffected individuals and 2) specific H3 receptor-dependent basophil mediator release, using an H3 receptor agonist and antagonist. Basophil-rich leukocyte fractions were prepared by dextran sedimentation of venous blood from 19 patients with atopic dermatitis (five male, 14 female, mean age 30.6 years, range 19-59 years) and 15 unaffected individuals (five male, 10 female, mean age 27.6 years, range 19-50 years). Anti-IgE (0.78-78.0 micrograms/ml) stimulation of basophils induced a concentration-dependent release of histamine and leukotriene C4, but not prostaglandin D2. Histamine release was maximally induced by 7.8 micrograms/ml anti-IgE with no significant (Mann-Whitney U test) difference between atopic basophils (n = 17; 43.65 +/- 4.16% mean +/- SEM) and normal basophils (n = 13; 52.23 +/- 4.39%). LTC4 release was maximal from atopic basophils incubated with 2.6 micrograms/ml anti-IgE (n = 5; 0.99 +/- 0.29 pg/10(6) cells) and from normal basophils incubated with 0.78 microgram/ml anti-IgE (n = 5; 25.38 +/- 5.79 pg/10(6) cells). Anti-IgE-stimulated release of leukotriene C4 from atopic basophils was significantly less than from normal basophils at all concentrations (p < 0.05). Basophils were co-incubated with anti-IgE (2.6 and 7.8 micrograms/ml) and either the H3 receptor agonist, (R)alpha-methylhistamine (10(-8) and 10(-7) M), or the H3 receptor antagonist thioperamide (10(-6) and 10(-5) M). Neither drug modulated anti-IgE-induced release of histamine (atopics, n = 10; normals, n = 8). These results indicate 1) that basophils from adults with atopic dermatitis release the same amount of histamine as, but less leukotriene C4 than, basophils of unaffected adults and 2) that H3 receptors are not involved in anti-IgE release of histamine from basophils. These data do not support a role for increased basophil release of histamine as a mediator in the itch and erythema of atopic dermatitis in adults.

Characterization of histamine receptor sub-types regulating prostacyclin release from human endothelial cells.

1. The histamine receptor sub-types that are involved in the initiation and maintenance of prostacyclin (PGI2) release from human endothelial cells have been investigated. 2. Endothelial cells cultured from umbilical vein (HUVEC) were incubated with either histamine, the selective H1-receptor agonists, 2-methyl histamine (2-MeHA) or thiazolylethylamine (ThEA), the H1-agonist/H3-antagonist, beta-histidine (beta-His), the selective H2-agonist, dimaprit, the H2-agonist/H3-antagonist, impromidine, the selective H3-agonist, (R)alpha-methylhistamine ((R)alpha-MeHA) and the H3-antagonist, thioperamide. 3. The H1-agonists and the H3-agonist (R)alpha-MeHA induced a concentration (100 nM-1 mM) and time-dependent release of PGI2 as determined by radioimmunoassay for 6-keto-PGF1 alpha, but were less potent than histamine itself. The rank order of potency was the same following 30 min and 24 h incubation, i.e. histamine > ThEA > 2-MeHA >> beta-His > (R)alpha-MeHA. 4. Histamine and 2-MeHA (1 microM-1 mM), ThHEA (10 microM-1 mM) and (R)alpha-MeHA (1 mM), but not beta-His, induced a significantly greater increase in PGI2 release after 24 h incubation than after 30 min incubation (P < 0.05). 5. Neither the selective H2-agonist, dimaprit, nor the H2-agonist/H3-antagonist, impromidine alone induced release of PGI2. 6. The H1-antagonist, mepyramine (10 microM), abolished release of PGI2 induced by histamine, the H1-agonists and (R)alpha-MeHA but the H2-antagonist cimetidine (10 microM) and the H2/H3-antagonist, burimamide (10 microM) did not significantly modulate PGI2 release. 7. Although the H3-agonist (R)alphax-MeHA induced release of PGI2, it failed to modulate PGI2 release in the presence of histamine.8. Low concentrations of the H3-antagonist, thioperamide (100 nM) did not modulate histamine release of PGI2 at all but after 24 h incubation, thioperamide (10-4 M) partially reduced PGI2 release in the presence of histamine.9. These results indicate that PGI2 from HUVEC is initiated and maintained via histamine HI-receptor occupancy. There appears to be no involvement of either H2- or H3-receptors in this particular endothelial cell histaminergic response.