Rat Paw Edema Assay Research Articles

3‐O‐Substituted Benzyl Pyridazinone Derivatives as COX Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Design, syntheses, and evaluation of 2,3‐diphenylcycloprop‐2‐en‐1‐ones and oxime derivatives as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

AbstractA group of 2,3‐diphenylcycloprop‐2‐enes having a variety of substituents at the para‐position of the C‐2 phenyl ring (H, F), and C‐3 phenyl ring (H, F, SMe, SOMe, SO2Me), in conjunction with either a C‐1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of cycloprop‐2‐ene compounds exhibited significant analgesic activity, since 4% NaCl‐induced abdominal constriction was reduced by 43–90% at 30 min, and 41–100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of cycloprop‐2‐ene compounds exhibited AI activities in the inactive‐to‐modest activity range (0–26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3‐diphenylcycloprop‐2‐enes with respect to the C‐1 substituent was oxime>hydrogen>carbonyl>benzoyl hydrazone. 2,3‐Diphenylcycloprop‐2‐en‐1‐one oxime (20) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX‐1 and COX‐2 inhibition studies showed that 2,3‐diphenylcycloprop‐2‐en‐1‐one oxime (20) is a selective COX‐2 inhibitor (COX‐1 IC50>100 μM; COX‐2 IC50=2.94 μM; COX‐2 selectivity index>34). A molecular modeling study that docked the oxime (20) in the active site of the human COX‐2 isozyme showed that it binds in the vicinity of the mouth of the COX‐2 binding site with the O‐atom of the oxime (=N–OH) moiety separated from the NH2 group of Arg120 by about 3.65 Å. This orientation of the oxime compound (20) in the COX‐2 binding site could be due to a potentially strong ionic interaction between the =NOH oxime moiety and the guanidinium moiety of Arg120. Drug Dev. Res. 57:6–17, 2002. © 2002 Wiley‐Liss, Inc.

Synthesis and pharmacological profile of 6-methyl-3-isopropyl-2 H-1,2-benzothiazin-4(3 H)-one 1,1-dioxide derivatives: non-steroidal anti-inflammatory agents with reduced ulcerogenic effects in the rat

The new anti-inflammatory agents 6-methyl-3-isopropyl-2 H-1,2-benzothiazin-4(3 H)-one 1,1-dioxide 6a and its analogues 6b– f were synthesized from l-valine. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 6a– f (5–20 mg/kg, i.p.) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay in albino rats, and their effects are comparable to that of piroxicam (5 mg/kg, i.p.), used as a reference drug. The nature of the substituents on the sulfonamide nitrogen and those on position three had a pronounced effect on the anti-inflammatory activity. Studies of structure–activity relationships have led to selection of compound 2,6-dimethyl-3-isopropyl-1,2-benzothiazin-3,4-diol 1,1-dioxide 6f which exhibited the most potent activity (61.7% inhibition at 5 mg/kg, i.p. and ED 50=4.5 mg/kg, i.p.). Comparison of the gastrointestinal safety of compounds 6a– f with that of piroxicam showed a far better tolerability for our products. This comparison was based on the ulcer index and the pH of gastric content.

3- O-Substituted benzyl pyridazinone derivatives as COX inhibitors

New 3- O-substituted benzyl pyridazinone compounds have been synthesised and evaluated for their cyclooxygenase inhibitory activity and COX-2 selectivity. Among the compounds synthesised, three compounds ( 11b– 11d) have shown in vitro COX-2 selectivity. These compounds have been evaluated for their in vivo potential using carrageenan-induced rat paw edema assay. One compound ( 11b) showed 32% anti-inflammatory activity at 30 mg kg −1 dose.

Design, syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

AbstractA group of (Z)‐ and (E)‐1,1‐dihalo‐2‐(4‐substituted‐phenyl)‐3‐phenylcyclopropane [(Z)‐10, (E)‐11] stereoisomers having a variety of substituents (H, Br, Cl, F, NO2, SO2Me) at the para‐position of the C‐2 phenyl ring in conjunction with either two chloro or bromo substituents at C‐1 were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of compounds (10‐11) exhibited significant analgesic activity since 4% NaCl‐induced abdominal constriction was reduced by 44–73% at 30 min, and 48–77% at 60 min, post‐drug administration relative to the reference drugs aspirin and celecoxib (58 and 32% inhibition at 30 min post‐drug administration) for a 50 mg/kg intraperitoneal dose. In the 1,1‐dichloro group of compounds, a Cl or MeSO2 substituent at the para‐position of the C‐2 phenyl ring generally provided superior analgesic activity. The most active analgesic compound, (E)‐1,1‐dichloro‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane (11h) inhibited abdominal constriction by 72 and 77% at 30 and 60 min post‐drug administration, respectively. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of (Z)‐10 and (E)‐11 compounds exhibited AI activities in the inactive‐to‐moderate activity range (1.5–45% inhibition) for a 50 mg/kg oral dose. The AI potency order, with respect to the para‐substitutent on the C‐2 phenyl ring, for the (Z)‐10 compounds was NO2 > MeSO2 ≈ H ≥ Cl, and for the (E)‐11 compounds was H ≥ MeSO2 > Cl ≈ Br. (E)‐1,1‐dibromo‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane (11l), which was the most active AI compound, reduced inflammation by 45 and 37% at 3 and 5 h post‐drug administration, respectively. The (E)‐11 stereoisomer was generally a more potent AI agent than the corresponding (Z)‐10 stereoisomer. In vitro COX‐1 and COX‐2 inhibition studies showed that (E)‐1,1‐dichloro‐2‐(4‐nitrophenyl)‐3‐phenylcyclopropane (11c) inhibited COX‐1 (IC50 = 278.8 μM) and COX‐2 (IC50 = 80.5 μM) for a COX‐2 selectivity index of 3.5, whereas (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane (11h) was a more potent inhibitor of COX‐1 and COX‐2, but it was more selective for COX‐1 (COX‐1 IC50 = 0.59 μM, COX‐2 IC50 = 3.04 μM). A molecular modeling (docking) study for (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane (11h) on the active site of the human COX‐2 isozyme shows it binds in the center of the active site with the 1,1‐dichloro substituents oriented in the direction of the mouth of the channel towards Arg120, and the C‐2 MeSO2 moiety oriented towards the apex of the active site with the S‐atom of the MeSO2 substituent positioned about 6.56 Å inside the entrance to the secondary pocket (Val523) of COX‐2. In contrast, the corresponding (Z)‐10h stereoisomer assumes a different position in the COX‐2 binding site where the S‐atom of the MeSO2 moiety is near (4.02 Å) the Ser530 OH, but a much greater distance from the COX‐2 secondary pocket (Val523). The results from these docking studies are consistent with the observation that (E)‐11h is an inhibitor of both COX isozymes, whereas the (Z)‐10h stereoisomer is an inactive COX inhibitor (COX‐1 IC50 > 100 μM, COX‐2 IC50 > 200 μM). Drug Dev. Res. 55:79–90, 2002. © 2002 Wiley‐Liss, Inc.

New acetylenic furan derivatives: synthesis and anti-inflammatory activity

A series of acetylenic furan derivatives have been synthesized via Pd-catalyzed coupling reactions of 2-(alkyltelluro)furan with several terminal alkynes. These compounds showed good anti-inflammatory activity in the carrageenin-induced rat paw edema assay. This represents a new and efficient method for the synthesis of pharmacologically active compounds.

Activity Profile of Glycolamide Ester Prodrugs of Ibuprofen

Glycolamide esters of ibuprofen (I), namely, unsubstituted (II), N, N dimethyl (III), and N, N diethyl (IV), were synthesized and studied for different physicochemical, pharmacological, and toxicological properties. They were comparable with I in respect of anti-inflammatory and analgesic activity but did not exhibit reduction in the ulcerogenicity on oral administration. However, all three exhibited significantly better topical activity in carrageenan-induced rat paw edema assay. In the same assay, they provided significant protection against inflammation when applied at a site remote to the inflammation site.

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of methyl 2-methyl-2-[2-(4-benzoyl-5-phenyl-7-halo-2-azabicyclo[4.1.0]hept-3-ene)]acetates (10-15), and the related acetamide derivative (16), that possess a variety of C-7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic-antiinflammatory agents. The effect of the C-7 substituent(s) and the nature of the acetic acid ester (R 1 = OMe) or acetamide (R 1 = NH 2 ) moiety on analgesic activity was determined using a 4% NaCI-induced abdominal constriction assay. Compounds 10-16 inhibited writhing by 36-82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C-7 substituents was a determinant of analgesic activity in the 7,7-dihalo group of compounds where the relative activity profile was 7-Cl 2 > 7-Br 2 > 7-F 2 > 7-Cl,7-F, and for 7-monohalo compounds where the potency order was 7-Br > 7-Cl. Elaboration of the 7,7-dibromo methyl acetate ester (10) to the corresponding acetamide derivative (16) enhanced analgesic activity. The nature of the 7-halo substituent(s) in the 7,7-dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan-induced rat paw edema assay, where the relative potency order was 7-Br 2 > 7-Cl 2 > 7-F 2 > 7-Cl,7-F. The most potent 7,7-dibromo compound (10) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX-2 (IC 50 = 26.4 μM) and COX-1 (IC 50 = 227 μM) for a COX-2 selectivity index of 8.6. Docking 10 in the active site of human COX-2 showed it binds in the center of the COX-2 binding site with the C-5 phenyl ring oriented toward the acetylation site (Ser 530 ), and the phenyl group of the C-4 benzoyl moiety oriented in the vicinity of the COX-2 secondary binding pocket near Val 523 .

Inhibitory effects of cimicifugae rhizoma extracts on histamine, bradykinin and COX-2 mediated inflammatory actions.

Rhizoma Cimicifugae (RC) has been used traditionally to treat pain and inflammation in Korea. The present study was conducted to gain insights into the mechanism of action regarding analgesic and antiinflammatory activities of RC extracts. RC was first extracted with methanol. The methanol extract (A) was fractionated to an ether-soluble fraction (B) and a water-soluble fraction (C). Fraction C was fractionated to a butanol-soluble fraction (D) and a water-soluble fraction (E). Each fraction (100 mg/kg, i.p.) was tested for analgesic and antiinflammatory activities. Administration of fractions A and D caused dramatic analgesic effects based on acetic acid writhing and tail-flick assays. However, fraction E had an analgesic effect only based on the acetic acid writhing assay. Fractions A, D and E exerted antiinflammatory effects on the rat paw oedema assay. The fractions A, D, E had an inhibitory action on the bradykinin/histamine-mediated contractions of guinea-pig ileum. In addition, fractions A, D and E had the ability to inhibit the production of LPS-induced 6-keto-PGF1alpha production in macrophage cultures. Taken together, these results provide scientific evidence that RC extracts exert analgesic and antiinflammatory effects by inhibiting bradykinin/histamine mediated actions and inhibiting 6-keto-PGF1alpha induction.

Potent antiinflammatory 3-thiazole-4(5)-acetic acids of 1,2-benzisothiazole

A number of 1,2-benzisothiazole derivatives, having 2-thiazolyl-4(5)-acetic acid moiety attached to position-3 of 1,2-benzisothiazole nucleus, were prepared and evaluated as antiinflammatory agents. Some of these were found to possess excellent level of antiinflammatory activity in carrageenin-induced rat paw edema assay. A number of 1,2-benzisothiazole derivatives, having 2-thiazolyl-4(5)-acetic acid moiety attached to position-3 of 1,2-benzisothiazole nucleus were prepared and evaluated as potential antiinflammatory agents. Some of these were found to possess significant level of antiinflammatory activity

Synthesis and antiinflammatory activity of 5-(1,2-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides

A series of 5-[4-(1,2-dihydropyridyl)]-2 H-tetrazol-2-acetic acids 13–19, esters 4–12 and amides 20–22 were synthesized in order to investigate the effect of 1,2-dihydropyridyl substituents (R 1 = aryl, alkyl; R 2 = phenoxycarbonyl, 4-chlorobenzoyl, hydrogen) on antiinflammatory activity in the carrageenan-induced rat paw edema assay. Compounds possessing a dihydropyridyl C-2 phenyl or n-butyl substituent exhibited, in most cases, more potent activity. The dihydropyridyl N-1 substituent was a determinant of activity in both the acetic acid ester and acetic acid classes of compounds where the relative potency order was 4-chlorobenzoyl > phenoxycarbonyl. The difference in activity between acetic acid esters (R 3 = OMe) and the corresponding acetic acids (R 3 = OH) was usually small. A dihydropyridyl N-1 substituent is essential for activity since the N-unsubstituted compound 20 was inactive. 2-Methyl-2-[5-[4-(1-phenoxycarbonyl-2-phenyl-1,2-dihydropyridyl)]-2 H-tetrazol-2-yl} acetic acid 14 was the most potent antiinflammatory agent in the group, reducing inflammation 75% (75 mg/kg po dose) relative to ibuprofen's 52% inhibition (100 mg/kg po dose) at 5 h.

Syntheses and anti-inflammatory activity of novel oximes and O-acyloximes.

Novel oximes were prepared from the corresponding aldehyde or ketone in the usual way, and a number of oxime esters, O-lauroyl, O-2-pyridinecarbonyl, O-nicotinoyl, and O-isonicotinoyl oximes were synthesized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)-4-dimethylaminopyridine (DMAP) method or a mixed anhydride method, in our search for potent anti-inflammatory compounds. The anti-inflammatory activity of these compounds was assessed by the carrageenan-induced paw edema assay in rats. The oximes (4, 5, and 13), O-lauroyloxime 1L, O-nicotinoyloximes (1N, 2N, 3N, and 4N), O-isonicotinoyloxime 1I, and O-2-pyridinecarbonyloxime 7P showed higher anti-inflammatory potency than aspirin, a prostaglandin cyclooxygenase inhibitor.

Natural Protein Toxins Affecting Cutaneous Microvascular Permeability

Natural toxins are found widespread from animal, plant and micro-organism sources. Presented here in review are recently discovered natural protein toxins that have in some way been shown to affect the permeability of the cutaneous micro-vasculature or skin capillaries.Capillaries play a major role in the body by controlling the necessary normal balance of metabolites in the body's tissues and that of the blood. The trans-capillary exchanges of water and metabolites are regulated by the basal lamina, the internal activities of the endothelial cells and the driving forces on each side of the capillary wall. Edema, inflammation, urticaria, increased capillary permeability and cutaneous edema are conditions that are related. The main methods for detecting the increase in skin capillary permeability have been by using the rat paw edema assay, labelled albumin, or other detectable indicators.Natural venoms and toxins sources causing edema include mammals, reptiles, amphibians, fishes, invertebrates, plants, and micro-organisms. Not all the substances causing increased capillary permeability are proteins such as certain alkaloids (Plants, fungi, fire ants and others) and normal endogenous substances e.g. histamine, serotonin, acetylcholine, (plants, snakes, and others) and are not considered in this review.Recently, a large number of toxins (predominantly bacterial toxins) have been reported that produce increased cutaneous capillary permeability, some of which are known in some detail and selected toxins are discussed.These studies have helped to understand the toxins, provided for more effective treatments, and helped to improve our knowledge of the capillaries and endothelial cells.

Synthèse et activité anti-inflammatoire de (3,5-di- tert-butyl-4-hydroxybenzylidène) cyclanones et composés apparentés

Some (3,5-di- ert-butyl-4-hydroxybenzylidene) cyclanones were synthesized and evaluated for anti-inflammatory activity in carragenin-induced rat paw edema assay. These compounds are slightly less active than phenylbutazone. Their inhibitory effects in vitro on human platelet aggregation have been also examined. The present study shows that the inhibitor profile of the tested compounds on platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP) bears similarly to that of acetylsalicylic acid. The free radical scavenging activity against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical was measured by Electron Spin Resonance spectrometry. All the studied compounds scavenge the DPPH radical, dose dependently.

Action of Nimesulide on Rat Gastric Prostaglandins and Renal Function

Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID), was shown to be less ulcerogenic [dose inducing ulceration in 50% of rats (UD50) > 20 mg/kg orally] than indomethacin (UD50 = 1.6mg/kg orally) and, in contrast to indomethacin, to affect prostaglandin E2 (PGE2) [dinoprostone] and thromboxane A2 (TXA2) formation more potently in inflammatory exudate than in the gastric mucosa in rats. After administration for 3 consecutive days, nimesulide in doses of up to 9 mg/kg orally (about 7 times the anti-inflammatory dose in the carrageenan rat paw oedema assay) did not modify renal function parameters or urinary PGE2 concentrations. In contrast, indomethacin caused a significant increase in blood urea and urinary N-acetyl-β-glucosaminidase and proteins at doses of 9 mg/kg orally (about 3 times the anti-inflammatory dose in the carrageenan rat paw oedema assay), and also significant inhibition of urinary PGE2 concentrations at doses of 3 and 9 mg/kg orally. These results, which have been confirmed by clinical data, suggest that nimesulide has good gastric and renal tolerability.

Evaluation of some tetraalkylammonium gold(I) and gold(III) aurate salts for oral antiinflammatory and antiarthritic activity

A series of four tetraalkylammonium gold(III) salts, [R 4N] +[AuX 4] − (R  Et, Bu; X  Cl,Br) and five tetraalkylammonium gold(I) salts, [R 4N] +- [AuX 2] − [R  Et, Bu; X  Cl, Br, C 6H 5S, S-Glucose- (OAc) 4] were prepared, together with [(Et 3P) 2Au +]- [AuCl 2] − ( 16) and evaluated for their oral antiinflammatory [Au(III)] and antiarthritic activity [Au(I)] in comparison with the gold compounds auranofin [Et 3PAuS-Glucose(OAc) 4] (AF) and [(Et 3P) 2Au] +- Cl −( 4). Synthesis of the complexes [R 4N] +[AuX 2] − (R  Et, Bu; X  Cl, Br) was accomplished by reduction of the corresponding Au(IlI) complex with C 6H 5NHNH 2 (X  Cl) or acetone (X  Br). RS −displacement of Br − from [(Bu) 4N] +[AuBr 2] − gave the thiolates [(Bu 4)N] +[Au(SR) 2] − [R  C 6H 5; 2, 3, 4, 6- Glucose(OAc) 4]. Admixture in EtOH of [(Et 3P) 2Au] +Cl with HAuCl 4 gave 16. Evaluation of the four Au(Ill) salts in the carrageenan-induced rat paw edema assay at 20 mg of Au/kg showed little antiinflammatory activity on oral administration (p.o.). The five Au( I) complexes were found to be devoid of significant antiarthritic activity in the adjuvant-induced arthritic rat emodel upon oral administration. Moreover, serum gold levels were below 0.6 μg/ ml suggesting poor oral bioavailability. In contrast [(Et 3P) 2Au +] [AuCl 2] − ( 16) was found to be orally effective with serum Au levels of 5.6 μg/ml and demonstrated significant antiarthritic activity comparable to both AF and the salt 4.

Synthesis and biological activity of 2-adamantanone oxime carbamate derivatives.

AbstractThe synthesis of a number of new 2‐adamantanone oxime carbamate derivatives (7a‐h) is described. When tested in the carrageenin‐induced rat paw edema assay, some of the compounds exerted moderate anti‐inflammatory activity. In addition, the title 2‐adamantanone oxime carbamates showed in vitro antifungal activity against yeast and systemic mycoses and dermatophytes.

ChemInform Abstract: SYNTHESIS OF 5‐ARYL‐2H‐TETRAZOLES, 5‐ARYL‐2H‐TETRAZOLE‐2‐ACETIC ACIDS, AND ((4‐PHENYL‐5‐ARYL‐4H‐1,2,4‐TRIAZOL‐3‐YL)THIO)ACETIC ACIDS AS POSSIBLE SUPEROXIDE SCAVENGERS AND ANTIINFLAMMATORY AGENTS

AbstractSynthetisiert und auf antiinflammatorische Wirkung untersucht werden die Tetrazole (III), (V) und (VI) sowie die Triazole (IX) und (X).

ChemInform Abstract: SYNTHESES AND ANTI‐INFLAMMATORY AND ANALGESIC ACTIVITIES OF HYDROXAMIC ACIDS AND ACID HYDRAZIDES

AbstractDie nach literaturbekannten Verfahren hergestellten Hydroxamsäuren (Ia), (IIa) und (III) sowie ihre Cu‐ und Zn‐Komplexe als auch die Acylhydrazide (Ib) und (IIb) werden auf entzündungshemmende und analgetische Wirkung untersucht.

Synthesis and anti-inflammatory activity of 2,6-di-tert-butylphenols with a heterocyclic group at the 4-position. III.

A series of 2, 6-di-tert-butylphenols with azoles at the 4-position was synthesized and evaluated for anti-arthritic activity in adjuvant-induced arthritis (AA) assay. Some compounds were also examined for anti-inflammatory activity in carrageenin-induced rat paw edema assay (CIPE) and for analgesic activity in AcOH-induced writhing assay in mice. 4-(3, 5-Di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline (6b) (25mg/kg. p.o.) had about the same activity as indomethacin (2mg/kg, p.o.) in AA assay. Compound 6b (25mg/kg, p.o.) was as potent as phenylbutazone (50mg/kg, p.o.) and indomethacin (3mg/kg, p.o.) in CIPE and showed low acute toxicity (>1000mg/kg, mouse, >400mg/kg, rat). Compound 6b had radical-scavenging activity in vivo and in vitro, and showed mild inhibitory activity on delayed-type hypersensitivity. Thus 6b is a promising candidate as a new anti-arthritic agent. Detailed pharmacologic studies of 6b are under way.