Inhibition of polymorphonuclear leukocyte 5-lipoxygenase and platelet cyclooxygenase by alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolacto ne (KME-4), a new anti-inflammatory drug

The effect of alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), a new anti-inflammatory compound, on arachidonate lipoxygenase and cyclooxygenase was investigated. KME-4 showed a dose-dependent inhibition of 5-lipoxygenase activity in both the cytosol (IC50: 0.85 microM) and ionophore A23187-stimulated cells (IC50: 11.5 microM) of guinea pig peritoneal polymorphonuclear leukocytes. KME-4 was also found to inhibit rabbit platelet cyclooxygenase (IC50: 0.44 microM), but had no inhibitory effect on platelet 12-lipoxygenase at concentrations up to 100 microM, whereas BW755C inhibited both enzymes in the same range of concentrations. The results indicate that KME-4 is a dual 5-lipoxygenase and cyclooxygenase inhibitor which is different from BW755C in affecting 12-lipoxygenase. These effects may provide information for understanding the pharmacological activity of KME-4.     

Effect of alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), a new anti-inflammatory drug, on the established adjuvant arthritis in rats

The effect of alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), a new anti-inflammatory drug, on established adjuvant arthritis in rats was compared to that of indomethacin. When administered orally daily from days 14 to 27 starting on day 14 after the adjuvant (day 0), KME-4 (2 to 10 mg/kg) produced a dose-related reduction of the swelling of both injected and uninjected hindpaws, and it retarded body weight loss. The initiation of paw swelling after the cessation of therapy was not observed at either 5 mg/kg or 10 mg/kg of KME-4. On day 42 (15 days after discontinuation of dosing), KME-4 caused the recovery of organ weight, erythrocyte sedimentation rate (ESR) and serum albumin/globulin (A/G) ratio towards normal levels, and it also decreased radiographic bone damage scores in a dose-dependent manner. The results indicate that KME-4 produces the improvement of systemic symptoms in the established adjuvant arthritis. The results obtained with indomethacin were similar to those with KME-4. However, the degree of the efficacy of indomethacin (2 mg/kg) was lower than that of KME-4 (10 mg/kg) as judged by the measured parameters (ESR, serum A/G ratio and bone damage).     

Analgesic and anti-inflammatory activities in rats of alpha-(3,5-di-t-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its intestinal damage

alpha-(3,5-Di-t-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), an anti-inflammatory drug, possesses analgesic activity in rat models. In the acetic acid-induced writhing test, the oral ED50 values for KME-4, indomethacin, naproxen and ibuprofen were 5.2, 3.8, 7.0 and 18.6 mg kg-1, respectively, and the relative order of potency of these drugs correlated with their inhibitory effect on acetic acid-induced vascular permeability in rats. KME-4 also had analgesic activity in the tests of Randall-Selitto and adjuvant arthritic flexion, but the dose required was greater than that needed in the writhing test. KME-4 (10 mg kg-1 day-1 orally) has a preventive effect against adjuvant-induced arthritis in rats, and its efficacy was more potent than indomethacin (2 mg kg-1 day-1) as judged from various parameters determined. When administered orally to rats once daily for 12 days, KME-4 caused perforating ulceration of the small intestine but this action was less potent than the effect of indomethacin, naproxen and ibuprofen.     

The effect of alpha-(3,5-di-t-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), a new anti-inflammatory drug, on leucocyte migration in rat carrageenan pleurisy

KME-4,alpha-(3,5-di-t-butyl-4-hydroxybenzylidene)-gamma-buty rolactone was found to reduce the accumulation of leucocytes and exudate volume in the rat carrageenan pleurisy model. When administered orally 1 h before carrageenan, KME-4 (3-10 mg kg-1) induced a degree of inhibition of leucocyte migration almost equal to that of indomethacin (3-10 mg kg-1) in both 5 h and 24 h pleurisies. Furthermore, KME-4, when administered orally 5 h after the carrageenan, inhibited both monocyte numbers and exudate volume in a 24 h pleurisy and was more effective than indomethacin and BW755c which inhibited only monocyte migration. These results suggest that KME-4 has a differential anti-inflammatory activity. Dexamethasone (0.25 mg kg-1) showed strong inhibition of total cell numbers and exudate volume.     

Pharmacological properties of the novel non-steroidal antiinflammatory agent N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2 -one

The antiinflammatory activity of the novel pyrrolidin-2-one derivative N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-o ne (E-5110) was investigated and compared with those of indomethacin and piroxicam in various antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory activity of E-5110 on the carrageenin paw edema was similar to that of indomethacin, and half that of piroxicam. The chronic inflammatory responses in established adjuvant- and type II collagen-induced arthritis, which are widely used models of rheumatoid arthritis, were suppressed as effectively by E-5110 as by indomethacin and piroxicam. E-5110 decreased the pleural exudate volume and inhibited leucocyte infiltration in a reversed passive Arthus reaction more potently than indomethacin, suggesting that mediators other than prostaglandin E2 may play an important role in this inflammatory process. The analgesic potency of E-5110 against inflammatory pain was similar to that of indomethacin or piroxicam, but the antipyretic activity of E-5110 was more potent than that of the reference drugs. The ulcerogenic effect of E-5110 on rat gastric mucosa was less than those of indomethacin and piroxicam. In conclusion, E-5110 is a very potent antiinflammatory compound acting against various types of inflammation, and has a favorable therapeutic index.     

Synthesis and antiinflammatory activities of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones

A series of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones was synthesized and evaluated as candidate antiinflammatory/analgesic agents as well as dual inhibitors of prostaglandin and leukotriene synthesis. Some compounds that showed dual inhibitory activity were found to possess equipotent antiinflammatory activities to indomethacin, with reduced ulcerogenic effects. One of the compounds, N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-o ne, was found to have a wider safety margin than indomethacin or piroxicam, and was selected for detailed evaluation as a candidate drug for clinical application.     

Pharmacological properties of N-methoxy-3-(3,5-ditert-butyl-4-hydroxybenzylidene)-2-pyrrolidone (E-5110), a novel nonsteroidal antiinflammatory agent

The antiinflammatory activity of a novel pyrrolidone derivative E-5110 was investigated using anti-inflammatory, analgesic and antipyretic animal models in comparison to indomethacin (IND) and piroxicam (PIR). The acute antiinflammatory activity of E-5110 on carrageenin paw edema was similar to IND, and half of PIR. E-5110 inhibited the pleural exudate volume and leucocyte infiltration in a reversed passive Arthus reaction more potent than IND. The chronic inflammatory responses in the established adjuvant- and type II collagen-induced arthritis were suppressed by E-5110 similar to IND and PIR. The analgesic potency of E-5110 was similar to IND and PIR, but the antipyretic activity of E-5110 was more potent than that of IND, and slightly more potent than that of PIR. The ulcerogenic effect of E-5110 on rat gastric mucosa was less than that of the reference drugs.     

Inhibition of prostaglandin synthetase by tolmetin (Tolectin,McN-2559), a new non-steroidal anti-inflammatory agent

Tolmetin [1-methyl-5-p-tolouylpyrrole-2-acetic acid (McN-2559, Tolectin)] and several of its analogs were shown to be potent inhibitors of the synthesis of prostaglandin E₂ from arachidonic acid by bovine seminal vesicle prostaglandin synthetase in vitro. Kinetic studies indicated that tolmetin, like indomethacin and aspirin, inhibited the synthetase competitively with respect to substrate. Unlike most non-steroidal anti-inflammatory agents, however, tolmetin was a competitive reversible inhibitor, and did not promote a time-dependent inactivation of the prostaglandin synthetase. Tolmetin and these other 1-methyl-pyrrole acetic acids represent a new structural class of anti-inflammatory agents which inhibit prostaglandin synthetase.     

2-(3-Halogen-4-hydroxyphenyl)-1,4-napthoquinone derivatives from 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-analogs, potent 5-lipoxygenase inhibitors. 27. 1,4-Naphthoquinones]

A new simple and fast method for the synthesis of halogenated hydroxyphenyl naphthoquinones as potential 5-lipoxygenase (LOX) inhibitors is presented. While the aryl naphthoquinone 1, a potent 5-LOX inhibitor, with AlCl3 is debutylated to 2a and 2b, the oxidized cyclohexadienylidene derivative 3 reacts comparably by concomitant halogenation to 4a and with AlBr3 to 4b, respectively. As products of a side reaction of 6 with TiCl4 and BBr3 the tetracyclic benzo[b]naphthol[2,1-d]furan derivatives 8a and 8b are isolated. Selected compounds are investigated for 5-lipoxygenase inhibiting and antioxidative properties. There is a clear-cut correlation of both qualities in those compounds with a 3-OH function and with two, one or without any tert-butyl group at the phenyl moiety. In contrast the quinone 6 (3-Cl) and the dibenzofuran 8a are powerful 5-LOX inhibitors with only low antioxidative activity.     

Pharmacological properties of N-(3'',4''-dimethoxycinnamoyl) anthranilic acid (N-5''), a new anti-atopic agent.

1 N-(3'-4'-dimethoxycinnamoyl) anthranilic acid (N-5') exhibited a dose-dependent, potent inhibition of the passive cutaneous anaphylaxis (PCA) mediated by homocytotropic antibodies (HTA), which was hardly affected by anti-inflammatory agents such as phenylbutazone, indomethacin and prednisolone at any dose used. The HTA-induced PCA was significantly inhibited by combined treatment with diphenydramine and cyproheptadine. 2 Doses of N-5' which potently inhibited HTA-induced PCA inhibited only slightly the heterologous PCA produced by anti-bovine serum albumin (BSA) rabbit serum. This heterologous PCA was clearly inhibited by phenylbutazone, indomethacin and prednisolone. Diphenydramine and cyproheptadine, singly or combined inhibited the heterologous PCA only slightly. 3 The increased vascular permeability caused by histamine and 5-hydroxytryptamine was significantly inhibited by diphenyldramine or cyproheptadine, but not by N-5' and the anti-inflammatory agents used. 4 N-5' 150 mg/kg orally inhibited rat paw oedema induced by carrageenin by about 26% while phenylbutazone, indomethacin and prednisolone produced significant inhibition. 5 N-5' at concentrations of 100 and 1000 muM significantly inhibited (by about 52% and 95%, respectively) the histamine release from rat peritoneal cells induced by HTA; 10 muM N-5' had little effect. Histamine release was inhibited by phenylbutazone or indomethacin at 1000 muM but not at 100 muM. Prednisolone had no effect on histamine release at any of the concentrations used. 6 These findings suggest that the inhibition of the HTA-induced PCA by N-5' may be due to inhibition of histamine release and is clearly different from the actions of anti-inflammatory agents such as phenylbutazone, indomethacin and prednisolone.     

Pharmacological investigations of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M 73101), a new analgesic and anti-inflammatory drug

Analgesic, anti-inflammatory and other related actions of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101) were investigated in experimental animals, and the following results were obtained: Analgesic activity of M73101 was more potent than that of other anti-inflammatory drugs except for aminopyrine in phenylquinone test in mice. M73101 showed the most potent analgesic activity among the drugs tested in Randall-Selitto test in rats. The mode of analgesic action of M73101 resembled that of aminopyrine. M73101 possessed potent inhibitory activities on acute inflammatory edema and suppressed the permeability of capillary vessels. M73101 inhibited histamine release from isolated rat mast cells (in vitro) and rat skin (in vivo) by the condensation product of N-methyl-homoanisylamine formaldehyde (compound 48/80), and leucocyte emigration in carrageenin rat pleurisy. M73101 was much less active than phenylbutazone and other anti-inflammatory drugs in causing gastric lesion. Considering from therapeutic index, M73101 was found to be much superior to mepirizole, tiaramide, benzydamine, phenylbutazone and acetylsalicylic acid.     

Pharmacological studies on proglumetacin maleate, a new non-steroidal anti-inflammatory drug (4). Mode of action on anti-inflammatory activity

The possible mechanism of the anti-inflammatory activity of proglumetacin maleate (PGM), a new indomethacin (IND) derivative interacting with arachidonic acid (AA) metabolism, was investigated to elucidate the contributions of PGM itself and its two major metabolites, desproglumideproglumetacin maleate (DPP) and IND. PGM caused much less inhibition of PGE2 formation by sheep seminal vesicle microsomes (IC50 = 310 microM) and TXB2 formation by a washed rabbit platelet suspension (IC50 = 6.3 microM) than IND. DPP also caused less inhibition of cyclooxygenase than IND. Moreover, PGM had less effect on sodium arachidonate (SAA)-induced rat platelet aggregation ex vivo and AA-induced sudden death in rabbits than IND. These results show that PGM has anti-inflammatory activity after its conversion to the active metabolite IND. However, the inhibitory effects of PGM and DPP were as strong as that of IND on SAA- or collagen-induced rabbit platelet aggregation in vitro. These activities are considered to be associated with platelet membrane interaction. Moreover, unlike IND, PGM (IC50 = 1.5 microM) and DPP (IC50 = 16.3 microM) strongly inhibited 5-HETE formation by the cytosol of guinea pig polymorphonuclear leukocytes. This unique activity of PGM on 5-lipoxygenase may contribute to its anti-inflammatory activity.     

Biochemical and pharmacological properties of a new topical anti-inflammatory compound, 9-phenylnonanohydroxamic acid (BMY 30094)

Drugs which block the biosynthesis of leukotrienes and prostaglandins may have potential in the treatment of psoriasis and other skin diseases. The biochemical and anti-inflammatory activity of 9-phenylnonanohydroxamic acid (BMY 30094) is described. BMY 30094 inhibited human neutrophil 5-lipoxygenase with an IC50 of 5.7 microM. BMY 30094 also blocked human platelet cyclooxygenase and lipoxygenase with IC50 values of 15.2 and 15.0 microM, respectively. Topical application of this compound blocked arachidonic acid and 12-O-tetradecanoylphorbol ester-induced mouse skin inflammation with activity comparable to that observed for lonapalene. The topical ED50 for BMY 30094 in the arachidonic acid-induced inflammation model is 2.2 mumoles/ear. In the sub-cutaneous carrageenan sponge assay in rats, BMY 30094 blocked LTB4 and PGE2 production and inhibited neutrophil migration. This compound would be a useful tool to determine the role of arachidonic acid metabolites in the etiology of inflammatory dermatoses.     

Pharmacological studies on proglumetacin maleate, a new non-steroidal anti-inflammatory drug. (1). Anti-inflammatory effects

Anti-inflammatory effects of proglumetacin maleate (PGM), a new indomethacin (IND) derivative, were compared with those of IND on an equimolar-dose basis. PGM produced a dose-dependent inhibition of vascular permeability and carrageenin edema. These inhibitory effects of PGM were greater when given 4 hr prior to phlogistic agents than when given 1 hr before. Moreover, these effects of PGM were long-acting. Inhibitory effects of PGM on kaolin edema and UV-erythema were slightly less active than those of IND. PGM markedly reduced the leukocyte migration in carrageenin pleurisy. Subacute anti-exudative and anti-granuloma effects of PGM were nearly equal to those of IND. Also, PGM showed strong prophylactic and therapeutic effects on adjuvant arthritis, the model of chronic (immuno-reactive) inflammation. These effects of PGM were superior or equal to those of IND. These pharmacological properties of PGM suggested its potential usefulness in rheumatic and other inflammatory disorders. It was considered that the mode of action of PGM mainly depended on its active metabolite, IND. However, PGM was also active in the case of local administration into the sites of inflammation on rat hind paw edema. Therefore, it seemed that PGM had a different behavior than a so called "prodrug".     

Hypocholesterolaemic and antiatherosclerotic effects of tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (SR-9223i)

Tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (CAS 126411-13-0, SR-9223i) is a member of a new class of compounds with multiple antiatherosclerotic activities. This report not only describes the cholesterol-lowering properties in four species of animals fed normocholesterolaemic diets but also reductions in lipid deposition in the arteries of cholesterol-fed New Zealand white rabbits following the administration of SR-9223i. Plasma cholesterol concentrations were reduced in mice by 27% (200 mg/kg/day administered in the diet for 10 days), in hamsters by 33% (200 mg/kg/day administered in the diet for 8 days), in dogs by 16% (25 mg/kg/day p.o. for 28 days) and 23% (75 mg/kg/day p.o. for 28 days) and in monkeys by 22% (25 mg/kg/day p.o. for 28 days). Further, the deposition of cholesterol, especially in the esterified form, in the aortae of cholesterol-fed New Zealand white rabbits was inhibited by SR-9223i (50 and 100 mg/kg/day p.o.). At the higher dose, the cholesteryl ester content of the aorta was half that of control animals. SR-9223i, at both doses, also inhibited the accumulation of cholesterol in the liver. SR-9223i has been shown to suppress HMG CoA reductase activity, inhibit ACAT activity and prevent lipid oxidation. These activities, demonstrated in vitro, have now been shown to translate into lipid lowering and antiatherosclerotic activities in vivo.     

6-(4-methyl-1-piperazinyl)morphanthridine (perlapine), a new tricyclic compound with sedative and sleep-promoting properties

Pharmacological studies of perlapine, a new dibenzoheteroepine derivative, have shown that its most prominent effects are depression of motor activity, central muscle-relaxation, and an increase in the telencephalic sleep phase as demonstrated by the EEG of the rat.Perlapine, though structurally related to some of the antipsychotic neuroleptics, does not exhibit to any marked degree the effects characteristic of that class of agents. One effect which distinguishes perlapine from the potent antipsychotic neuroleptics and also from the benzodiazepines is its strong inhibitory action on the reticular formation. This effect is thought to be a major factor in the sleep-promoting action of the drug.Chronic (4-week) EEG-studies of perlapine in the rat provided no evidence to suggest the development of tolerance.It is concluded that the mechanism of action of perlapine differs from that of other sleep-promoting agents.U.S. Adopted Name and British Approved Name, Code Number: HUF-2333.     

The antiinflammatory profile of (5H-dibenzo[a,d]-cyclohepten-5-ylidene)acetic acid (WY-41,770), an agent possessing weak prostaglandin synthetase inhibitory activity that is devoid of gastric side effects

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.