Carrageenan-induced Rat Paw Edema Assay Research Articles

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.

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 .

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.

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.

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: SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF POLY(OXYETHYLENE) DERIVATIVES OF 4‐ISOBUTYLPHENYL‐2‐PROPIONIC ACID (IBUPROFEN)

AbstractGemäß Formelschema werden die oligomeren Derivate (V), (VIIa) und (VIIb) dargestellt, die gegenüber Ibuprofen (I)‐l: ‐ei‐ oraler Anwendun eine län er dauernde antiinflammatorische Wirkun zei en.

Synthesis and pharmacological evaluation of poly(oxyethylene) derivatives of 4-isobutylphenyl-2-propionic acid (ibuprofen)

The synthesis of three oligomeric derivatives of 4-isobutylphenyl-2-propionic acid (ibuprofen), namely, the monoester of tetraethylene glycol (I) and the diesters of poly(oxyethylene) samples having molecular weights of 1000 (+/- 50) and 2000 (+/- 150) (II and III), has been performed via the imidazolide method. The antiinflammatory activity of I-III, and of equivalent amounts of free drug, was determined in the carrageenan-induced rat paw edema assay at different times after oral administration and found to be considerably prolonged in the case of the three derivatives. The lowest molecular weight derivative (I) also had an enhanced initial activity with regard to 4-isobutylphenyl-2-propionic acid. These results were confirmed by measuring the plasma levels of 4-isobutylphenyl-2-propionic acid in rats at different times after oral administration.

2-Substituted azole derivatives. 1. Synthesis and antiinflammatory activity of some 2-(substituted-pyridinyl)benzimidazoles

A series of 2-(2-pyridinyl)benzimidazoles was synthesized and evaluated for antiinflammatory activity by the carrageenan-induced rat paw edema assay. Among several active derivatives, 2-(5-ethylpyridin-2-yl)benzimidazole (6) was selected for further study. A comparison of compound 6 with phenylbutazone and tiaramide revealed that 6 possesses stronger activity in acute inflammatory models possibly with slightly less gastrointestinal irritation than both phenylbutazone and tiaramide.

ChemInform Abstract: SYNTHESIS OF CARBOXYARYLINDOLES AND BENZOFURANS AS NONSTEROIDAL ANTIINFLAMMATORY AGENTS

AbstractPhenacylbromide (I) kondensieren mit Enaminen (II) zu den 2‐Phenacy1‐ ketonen (III), aus denen sauer die anellierten Furane (IV) und mit Aminen die analogen Pyrrole (V) gebildet werden.

Synthesis and antiinflammatory activity of some 2-substituted 4- and 7-benzoxazoleacetic and .alpha.-methylacetic acids

4- and 7-benzoxazoleacetic and alpha-methylacetic acids substituted in the 2 position with phenyl and substituted phenyl groups have been synthesized and tested on the carrageenan-induced rat paw edema assay. The only compound found to have significant activity, albeit of a low order, was 2-phenyl-alpha-methyl-7-benzoxazoleacetic acid.

ANTI‐INFLAMMATORY AND IRRITANT EFFECTS OF A FRACTION FROM NORMAL HUMAN PLASMA

1 By the use of carrageenan-induced rat paw oedema assay the anti-inflammatory activity of a fraction isolated from normal human plasma has been measured after its intravenous, intraperitoneal and oral administration. Its effects in the dextran-induced rat paw oedema and the systemic dextran anaphylactoid reaction in the rat were also studied.2 The fraction showed marked anti-inflammatory activity in the carrageenan test after intravenous administration and a smaller but still significant activity when given intraperitoneally, but was inactive orally after the administration of a larger dose. It was active in the dextran-induced paw oedema test but not against the anaphylactoid reaction.3 A comparison between its anti-inflammatory and irritant properties revealed no correlation when each parameter was determined in relation to dose. The fraction did not affect the blood pressure of the anaesthetized rat.4 These findings are discussed in relation to the existence of a natural anti-inflammatory substance or substances in human plasma.