共查询到20条相似文献,搜索用时 15 毫秒
1.
Navidpour L Shadnia H Shafaroodi H Amini M Dehpour AR Shafiee A 《Bioorganic & medicinal chemistry》2007,15(5):1976-1982
A new type of 1-aryl-5-(4-methylsulfonylphenyl)imidazoles, possessing C-2 alkylthio (SMe or SEt) substituents, were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. The compound, 1-(4-bromophenyl)-5-(4-methylsulfonylphenyl)-2-methylthioimidazole (11g), was the most potent and selective COX-2 inhibitor (COX-2 IC50=0.43 microM with no inhibition of COX-1 up to 25 microM) relative to the reference drug celecoxib (COX-2 IC50=0.21 microM with no inhibition of COX-1 up to 25 microM) and also showed very good anti-inflammatory activity compared to celecoxib in carrageenan-induced rat paw edema assay. 相似文献
2.
Uddin MJ Rao PN Rahim MA McDonald R Knaus EE 《Bioorganic & medicinal chemistry letters》2004,14(19):4911-4914
A new class of (E)-2-alkyl-2-(4-methanesulfonylphenyl)-1-phenylethenes were designed for evaluation as selective cyclooxygense-2 (COX-2) inhibitors. The target olefins were synthesized, via a Takeda olefination reaction, followed by oxidation of the respective thiomethyl olefinic intermediate. In vitro COX-1/COX-2 inhibition studies identified (E)-2-(4-methanesulfonylphenyl)-1-phenyloct-1-ene (8d) as a potent (IC(50)=0.77 microM) and selective (Selectivity Index>130) COX-2 inhibitor. 相似文献
3.
Two series of 4-benzylideneamino- and 4-phenyliminomethyl-benzenesulfonamide derivatives were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors in a cellular assay using human whole blood (HWB). Extensive structure-activity relationships (SAR) were studied within these series. Several compounds were found to be novel and selective COX-2 inhibitors. Among them, the most potent and selective was 4-(3-carboxy-4-hydroxy-benzylideneamino)benzenesulfonamide (20, LA2135), (IC(50)'s for COX-1: 85.13 microM; COX-2: 0.74 microM; SI: 114.5), being more active COX-2 selective than celecoxib. 相似文献
4.
Zarghi A Zebardast T Hakimion F Shirazi FH Rao PN Knaus EE 《Bioorganic & medicinal chemistry》2006,14(20):7044-7050
A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO(2)NH, or N(3), COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO(2)NH COX-2 pharmacophore, (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2 IC(50)=1.0 microM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC(50)=0.50 microM; SI>200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N(3) COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC(50)=22.2 microM; COX-2 IC(50)=0.3 microM; SI=60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO(2)NH and N(3) substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity. 相似文献
5.
Zarghi A Kakhgi S Hadipoor A Daraee B Dadrass OG Hedayati M 《Bioorganic & medicinal chemistry letters》2008,18(4):1336-1339
A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC(50)=0.11 microM) with a high COX-2 selectivity index (SI=203.6) comparable to the reference drug celecoxib (COX-2 IC(50)=0.06 microM; COX-2 SI=405). The structure-activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity. 相似文献
6.
A group of celecoxib analogues in which the para-SO(2)NH(2) substituent on the N(1)-phenyl ring was replaced by a para-sulfonylazido (SO(2)N(3)) 4, or a meta-SO(2)N(3) 8, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO(2)N(3) substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a) having a meta-SO(2)N(3) substituent (COX-1 IC(50) >100microM; COX-2 IC(50)=5.16microM; COX-2 selectivity index >19.3) is a selective COX-2 inhibitor. A molecular modeling (docking) study showed that the SO(2)N(3) group of 8a inserts deep inside the secondary pocket of the COX-2 binding site. The SO(2)N(3) moiety of 8a can undergo a dual H-bonding interaction via one of its SO(2) oxygen-atoms, and an electrostatic (ion-ion) interaction via the terminal azido (N(3)) nitrogen-atom, to the guanidino NH(2) of Arg(513) in the secondary pocket of COX-2. These observations indicate that an appropriately positioned SO(2)N(3) moiety is a novel alternative bioisostere to the traditional SO(2)NH(2) and SO(2)Me pharmacophores present in selective COX-2 inhibitors, that are only capable of H-bonding interactions with the COX-2 isozyme, for use in drug design. 相似文献
7.
A group of regioisomeric (E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target (E)-1,3-diarylprop-2-en-1-ones were synthesized via a Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified (E)-1-(4-methanesulfonylphenyl)-3-(4-methylphenyl)prop-2-en-1-one (9f) as a potent COX-2 inhibitor (IC50=0.3 microM) with a high COX-2 selectivity index (SI=106) comparable to that of the reference drug rofecoxib (COX-2 IC50=0.5 microM; COX-2 SI>200). A molecular modeling study where 9f was docked in the binding site of COX-2 showed that the para-SO2Me substituent on the C-1 phenyl ring is oriented in the vicinity of the secondary COX-2 binding site near Val523. The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design novel acyclic 1,3-diarylprop-2-en-1-ones with selective COX-2 inhibitory activity. 相似文献
8.
A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO(2)Me pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target linear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation of the respective 1-(methylthiophenyl)-2-phenylacetylene intermediate. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12d) as a potent COX-2 inhibitor (IC(50) = 0.32 microM) with a high COX-2 selectivity index (SI > 320) comparable to the reference compound rofecoxib (COX-2 IC(50) = 0.50 microM; COX-2 SI > 200). A molecular modeling study where (12d) was docked in the binding site of COX-2 showed that the MeSO(2) COX-2 pharmacophore was positioned in the vicinity of the secondary COX-2 binding site near Val(523). The 1-(4-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene (11f, COX-1 IC(50) = 1.00 microM; COX-2 IC(50) = 0.06 microM; COX-2 SI = 16.7) and 1-(3-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene (12f, COX-1 IC(50) = 6.5 microM; COX-2 IC(50) = 0.05 microM; COX-2 SI = 130) regioisomers exhibited comparable COX-2 inhibition, and moderately lower selective COX-2 selectivity, relative to the reference drug celecoxib (COX-1 IC(50) = 33.1 microM; COX-2 IC(50) = 0.07 microM; COX-2 SI = 472). The most potent anti-inflammatory agent 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12d) exhibited moderate oral anti-inflammatory activity (ED(50)= 129 mg/kg) at 3 h postdrug administration relative to the reference drug celecoxib (ED(50) = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. The structure-activity data acquired indicate that the acetylene moiety constitutes a suitable scaffold (template) to design novel acyclic 1,2-diarylacetylenes with selective COX-2, or dual COX-1/COX-2, inhibitory activities. 相似文献
9.
Ranatunge RR Earl RA Garvey DS Janero DR Letts LG Martino AM Murty MG Richardson SK Schwalb DJ Young DV Zemtseva IS 《Bioorganic & medicinal chemistry letters》2004,14(24):429-6052
A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4–10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 μM and COX-2: 1.2 μM). 相似文献
10.
Orjales A Mosquera R López B Olivera R Labeaga L Núñez MT 《Bioorganic & medicinal chemistry》2008,16(5):2183-2199
New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure-activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC(50)=2.4-0.3nM and 80- to 780-fold more selective than rofecoxib). 相似文献
11.
Ranatunge RR Garvey DS Janero DR Letts LG Martino AM Murty MG Richardson SK Young DV Zemetseva IS 《Bioorganic & medicinal chemistry》2004,12(6):1357-1366
Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human whole blood (HWB). Several of the compounds were found to be novel and selective COX-2 inhibitors, the most potent and selective being 1-(5-cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene, 7a (IC(5o) for COX-1>100 microM; for COX-2=1.3 microM). 相似文献
12.
A group of acyclic 2-alkyl-1,1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC(50) = 0.014 microM), and an extremely selective [COX-2 selectivity index (SI) > 7142], COX-2 inhibitor that showed superior anti-inflammatory (AI) activity (ID(50) = 2.5 mg/kg) relative to celecoxib (ID(50) = 10.8 mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC(50) = 2.4 microM; COX-2 IC(50) = 0.03 microM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID(50) = 4.1mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO(2)Me substituent of (Z)-13b inserts deep inside the 2 degrees -pocket of the COX-2 active site, where one of the O-atoms of SO(2) group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(120), Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)-olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2. 相似文献
13.
The inhibitory effects of the synthetic serotonin analogues (1-8) on COX (1 and 2) were evaluated. Two serotonin derivatives (4 and 8) showed inhibitory effect of COX (1 and 2). Especially, 4 exhibited excellent inhibitions on COX-2 with extremely high potency (IC(50)=42.5 μM). The inhibitory activities of cinnamic acid derivatives and serotonin were evaluated to clarify whether inhibitory activities of compound 4 and 8 are due to cinnamic acid moiety or serotonin moiety. Caffeic acid and N-caffeoyl serotonin (4) exhibited selective inhibition of COX-2 compared to aspirin. Comparison caffeic acid with 4 suggested that the linkage of caffeic acid and serotonin enhance COX-2 inhibition. Comparison of structures of caffeic acid and sinapic acid implied that catechol moiety of cinnamic acid derivatives is a major contributing factor for selective inhibition of COX-2. The selective COX-2 inhibitory activity of compound 4 is significant and could be employed as drugs against inflammatory and allergy. 相似文献
14.
Tsai WJ Shiao YJ Lin SJ Chiou WF Lin LC Yang TH Teng CM Wu TS Yang LM 《Bioorganic & medicinal chemistry letters》2006,16(17):4440-4443
A series of phenylazobenzenesulfonamide derivatives were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors in a cellular assay using human whole blood (HWB) and an enzymatic assay using purified ovine enzymes. Extensive structure-activity relationships (SAR) were studied within this series, and several of selective COX-2 inhibitors have been identified. Among them, compound 8, 4-(4-amino-2-methylsulfanyl-phenylazo)benzenesulfonamide, showed a potent inhibitory activity to the cyclooxygenase enzymes (IC(50)'s for COX-1: 23.28 microM; COX-2: 2.04 microM), being active but less COX-2 selective than celecoxib. 相似文献
15.
El-Sayed MA Abdel-Aziz NI Abdel-Aziz AA El-Azab AS ElTahir KE 《Bioorganic & medicinal chemistry》2012,20(10):3306-3316
New pyrazole and pyrazoline derivatives have been synthesized and their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. Among the tested compounds, N-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)-3,5-bis(trifluoromethyl)aniline 8d exhibit optimal COX-2 inhibitory potency (IC(50)=0.26 lM) and selectivity (SI)=>192.3] comparable with reference drug celecoxib (IC(50) value of 0.28 lM and selectivity index of 178.57). Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using carrageenan-induced rat paw edema model. Molecular modeling was conducted to study the ability of the active compounds to bind into the active site of COX-2 which revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. 相似文献
16.
A group of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides, possessing either a F or a substituted-phenyl ring substituent (4-F, 2,4-F2, 4-SO2Me, 4-OCHMe2) attached to its C-4 or C-6 position, was prepared using a palladium-catalyzed Suzuki cross-coupling reaction for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Although N-acetyl-3-carboxymethyl-6-fluorobenzenesulfonamide [14, COX-1 IC50 = 2.26 microM; COX-2 IC50 = 0.012 microM; COX-2 selectivity index (SI) = 188] and N-acetyl-3-carboxymethyl-6-(4-isopropoxyphenyl)benzenesulfonamide (20c, COX-1 IC50 >100 microM; COX-2 IC50 = 0.15 microM; COX-2 SI >667) exhibited potent in vitro COX-2 inhibitory activity and high COX-2 selectivity, both compounds were inactive anti-inflammatory agents in a carrageenan-induced rat paw edema assay. In contrast, the less potent and less selective COX-2 inhibitors N-acetyl-2-carboxymethyl-4-fluorobenzenesulfonamide (12, COX-1 IC50 = 4.25 microM; COX-2 IC50 = 0.978 microM; COX-2 SI = 4.3), N-acetyl-2-carboxymethyl-4-(2,4-difluorophenyl)benzenesulfonamide (17c, COX-1 IC50 = 1.02 microM; COX-2 IC50 = 1.00 microM; COX-2 SI = 1.02), and N-acetyl-3-carboxymethyl-6-(4-methanesulfonylphenyl)benzenesulfonamide (20e, COX-1 IC50 = 0.109 microM; COX-2 IC50 = 1.14 microM; COX-2 SI = 0.095) exhibited moderate anti-inflammatory activity where a 75 mg/kg oral dose reduced inflammation 26%, 14%, and 20%, respectively, at 3 h postdrug administration relative to the reference drug aspirin where a 50 mg/kg oral dose reduced inflammation by 25% at 3 h postdrug administration. 相似文献
17.
4-[4-(N-Acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone, possessing a N-acetylsulfonamido pharmacophore, has been identified as a potent and selective COX-2 inhibitor that has the potential to acetylate the COX-2 isozyme. 相似文献
18.
A group of novel (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)oct-1-ene (8d) as a highly potent (IC50=0.03 microM), and an extremely selective [COX-2 SI (selectivity index)>3,333], COX-2 inhibitor that showed good anti-inflammatory (AI) activity (ID50=2.8 mg/kg). A molecular modeling (docking) study showed that the p-MeSO2NH group present in (Z)-8d inserts deep inside the 2 degrees-pocket of the COX-2 binding site, it undergoes a hydrophobic interaction with Ala516 and Gly519, and one of the O-atoms of the MeSO2 group participates in a weak hydrogen bonding interaction with the NH2 of Arg513 (distance= 3.85 angstroms). Similar in vitro COX-1/COX-2 enzyme inhibition studies showed that the azido compound 1-(4-azidophenyl)-1,2-diphenyloct-1-ene (9c) is also a potent and selective COX-2 inhibitor (COX-2 IC50=0.11 microM: SI>909) that exhibits good AI activity (ID50=5.0 mg/kg). A docking experiment to determine the orientation of (Z)-9c within the COX-2 binding site showed that the linear p-N3 group inserts into the COX-2 2 degrees-pocket, where it undergoes an ion-ion (electrostatic) interaction with Arg513. Structure-activity data acquired indicate that an olefin having either a C-1 p-MeSO2NH-phenyl, or a p-N3-phenyl, substituent, that is, cis to a C-2 unsubstituted phenyl substituent, in conjunction with C-1 unsubstituted phenyl and C-2 alkyl substituents, provides a novel template to design acyclic olefinic COX-2 inhibitors. 相似文献
19.
D Dubé C Brideau D Deschênes R Fortin R W Friesen R Gordon Y Girard D Riendeau C Savoie C C Chan 《Bioorganic & medicinal chemistry letters》1999,9(12):1715-1720
A series of novel 2-alkoxy, 2-thioalkoxy and 2-amino-3-(4-methylsulfonyl)phenylpyridines has been synthesized and shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. Structure-activity relationship studies have demonstrated that central pyridine ring substituents play an important role in the COX-2 potency, selectivity vs the COX-1 enzyme, and oral activity. 相似文献
20.
N-Acetyl-2-carboxybenzenesulfonamide (11), and a group of analogues possessing an appropriately substituted-phenyl substituent (4-F, 2,4-F(2), 4-SO(2)Me, 4-OCHMe(2)) attached to its C-4, or C-5 position, were synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 inhibition studies showed that 11 is a more potent inhibitor (COX-1 IC(50)=0.06microM; COX-2 IC(50)=0.25microM) than aspirin (COX-1 IC(50)=0.35microM; COX-2 IC(50)=2.4microM), and like aspirin [COX-2 selectivity index (S.I.)=0.14], 11 is a nonselective COX-2 inhibitor (COX-2 S.I.=0.23). Regioisomers having a 2,4-difluorophenyl substituent attached to the C-4 (COX-2 IC(50)=0.087microM; COX-2 S.I. >1149), or C-5 (COX-2 IC(50)=0.77microM, SI>130), position of 11 exhibited the most potent and selective COX-2 inhibitory activity relative to the reference drug celecoxib (COX-1 IC(50)=33.1microM; COX-2 IC(50)=0.07microM; COX-2 S.I.=472). N-Acetyl-2-carboxybenzenesulfonamide (11, ED(50)=49 mg/kg), and its C-4 2,4-difluorophenyl derivative (ED(50)=91 mg/kg), exhibited superior antiinflammatory activity (oral dosing) in a carrageenan-induced rat paw edema assay compared to aspirin (ED(50)=129 mg/kg). These latter compounds exhibited comparable analgesic activity to the reference drug diflunisal, and superior analgesic activity compared to aspirin, in a 4% NaCl-induced abdominal constriction assay. A molecular modeling (docking) study indicated that the SO(2)NHCOCH(3) substituent present in N-acetyl-2-carboxy-4-(2,4-fluorophenyl)benzenesulfonamide, like the acetoxy substituent in aspirin, is suitably positioned to acetylate the Ser(530) hydroxyl group in the COX-2 primary binding site. The results of this study indicate that the SO(2)NHCOCH(3) pharmacophore present in N-acetyl-2-carboxybenzenesulfonamides is a suitable bioisostere for the acetoxy (OCOMe) group in aspirin. 相似文献