Inhibition of mammalian 5-lipoxygenase by 2-benzylaminophenols.

A number of 2-benzylaminophenols, prepared from the corresponding 2-aminophenols by reductive alkylation, have been identified as highly potent inhibitors of 5-lipoxygenase with IC50 values in the nanomolar range. Most compounds were also shown to inhibit the release of the peptidoleukotrienes when administered intraperitoneally in a rat model of peritoneal anaphylaxis. Two compounds evaluated for their effects on anaphylactic contractions in isolated human lung were shown to attenuate the leukotriene-induced component of the response.

Novel 1H-benzimidazol-4-ols with potent 5-lipoxygenase inhibitory activity.

The synthesis and structure--activity profile of 2-substituted benzimidazol-4-ols as inhibitors of cell-free RBL-1 5-lipoxygenase are discussed, and their potency is compared with that of the standard inhibitors phenidone, AA 861, BW 755C, and nordihydroguaiaretic acid. In contrast to the standard compounds, most did not inhibit the release of slow-reacting substance of anaphylaxis (SRS-A) in vivo when administered at 200 microM ip to rats subjected to peritoneal anaphylaxis, although five compounds containing a methoxylated benzyl group (compounds 36, 39, 42, and 43) or hydroxylated benzyl group (41) showed similar activity to that of phenidone, nordihydroguaiaretic acid, and AA 861. Of the many compounds tested, two, 5-tert-butyl-7-methyl-2-(trifluoromethyl)-1H-benzimidazol-4-ol (57) and 2-(4-methoxybenzyl)-7-methyl-1H-benzimidazol-4-ol (36), like dexamethasone, inhibited monocyte accumulation in a pleural exudate model of inflammation. Standard lipoxygenase inhibitors such as phenidone, BW 755C, and AA 861 were inactive in this system.

Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs.

Recent studies suggest that thermogenesis in brown adipose tissue has an important role in the regulation of energy balance. Thermogenesis is effected by noradrenaline released from sympathetic nerve endings; the noradrenaline stimulates beta-adrenoceptors, causing lipolysis, and the released fatty acids then promote the uncoupling of oxidative phosphorylation from electron transport. It has been widely accepted that mammalian beta-adrenoceptors exist as two subtypes, beta 1 and beta 2, and rat brown adipocyte beta-adrenoceptors have been classed as beta 1 or as a mixed beta 1/beta 2 population. The beta 1 subtype predominates in atria, whereas the beta 2 subtype predominates in trachea. However, we have now found a novel group of beta-adrenoceptor agonists that selectively stimulate lipolysis in brown adipocytes. In contrast, isoprenaline, fenoterol and salbutamol are less potent as stimulants of lipolysis than as stimulants of atrial rate or tracheal relaxation. Therefore, beta-adrenoceptors in rat brown adipocytes are of neither the beta 1 nor beta 2 subtypes. Compounds that selectively stimulate brown adipocyte beta-adrenoceptors should have potential as thermogenic anti-obesity agents and this has been demonstrated with BRL 26830A , BRL 33725A and BRL 35135A .

Treatment of obesity with thermogenic beta-adrenoceptor agonists: studies on BRL 26830A in rodents.

Studies on BRL 26830A in rodents have shown that thermogenic beta-adrenoceptor agonists have potential for the therapy of obesity. BRL 26830A reduced body weight gain in ob/ob mice and fa/fa rats by reducing lipid accumulation. It had no effect on lean body mass. BRL 26830A did not reduce food intake, its anti-obesity effect being due to stimulation of energy expenditure. This thermic effect was enhanced in the obese animals by repeat dosing. BRL 26830A did not affect body weight gain in the lean counterparts of the obese animals because its thermic effect in lean animals was reduced by repeat dosing. Brown adipose tissue is an important site of BRL 26830A-induced thermogenesis. A single dose of BRL 26830A raised brown adipose tissue temperature, depleted brown adipose tissue lipid and unmasked GDP-binding sites in brown adipose tissue mitochondria. Repeat dosing caused hypertrophy of brown adipose tissue and improved cold tolerance in mice. In-vitro studies showed that the rat brown adipocyte beta-adrenoceptor does not fall into the beta 1/beta 2 classification and BRL 28410, which mediates the biological effects of BRL 26830A in vivo, selectively stimulated the brown adipocyte receptor. It is concluded that BRL 26830A achieves its anti-obesity effect by mimicking natural mechanisms involved in thermogenesis and the control of body weight.