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.
Plummer CW Finke PE Mills SG Wang J Tong X Doss GA Fong TM Lao JZ Schaeffer MT Chen J Shen CP Stribling DS Shearman LP Strack AM Van der Ploeg LH 《Bioorganic & medicinal chemistry letters》2005,15(5):1441-1446
Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight. 相似文献
3.
Scholz M Blobaum AL Marnett LJ Hey-Hawkins E 《Bioorganic & medicinal chemistry》2012,20(15):4830-4837
A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores. 相似文献
4.
J S Carter D J Rogier M J Graneto K Seibert C M Koboldt Y Zhang J J Talley 《Bioorganic & medicinal chemistry letters》1999,9(8):1167-1170
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition. 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.
Thalidomide and its analogues as cyclooxygenase inhibitors 总被引:6,自引:0,他引:6
Noguchi T Shimazawa R Nagasawa K Hashimoto Y 《Bioorganic & medicinal chemistry letters》2002,12(7):1043-1046
Thalidomide showed cyclooxygenase (COX)-1/2 inhibitory activity with a potency comparable to that of aspirin. Structural development studies of thalidomide resulted in potent COX-1/2 inhibitors, and COX-1-selective and COX-2-selective inhibitors. 相似文献
7.
J S Carter S Kramer J J Talley T Penning P Collins M J Graneto K Seibert C M Koboldt J Masferrer B Zweifel 《Bioorganic & medicinal chemistry letters》1999,9(8):1171-1174
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo. 相似文献
8.
Andrew F. Donnell Paul J. Dollings John A. Butera Arlene J. Dietrich Kerri K. Lipinski Afshin Ghavami Warren D. Hirst 《Bioorganic & medicinal chemistry letters》2010,20(7):2163-2167
Substituted pyridazino[4,5-b]indolizines were identified as potent and selective PDE4B inhibitors. We describe the structure–activity relationships generated around an HTS hit that led to a series of compounds with low nanomolar affinity for PDE4B and high selectivity over the PDE4D subtype. 相似文献
9.
Comparative gastrointestinal toxicity of selective cyclooxygenase (COX-2) inhibitors 总被引:1,自引:0,他引:1
Cyclooxygenase (COX-2) inhibitors were developed with the hope that they will cause fewer gastrointestinal adverse effects. Ability of selective as well as nonselective COX inhibitors to alter ischemia-reperfusion induced damage of gastric mucosa and hapten-induced colitis in rats has been compared. Celecoxib (10, 20 and 40 mg/kg(-l)) was significantly more potent at aggravating ischemia-reperfusion injury as compared to nimesulide. Similarly, celecoxib was found to maximally potentiate TNBS-induced colitis, followed by nimesulide and indomethacin. Celecoxib at its highest dose produced maximum deep histological injury. This paradoxic ulcer and colitis aggravating effect of selective COX-2 inhibitors may be explained by suppression of protective prostaglandins generated as a consequence of COX-2 induction in inflammatory states. 相似文献
10.
Zarghi A Najafnia L Daraee B Dadrass OG Hedayati M 《Bioorganic & medicinal chemistry letters》2007,17(20):5634-5637
A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. 相似文献
11.
12.
Pal M Rao Veeramaneni V Nagabelli M Rao Kalleda S Misra P Rao Casturi S Rao Yeleswarapu K 《Bioorganic & medicinal chemistry letters》2003,13(10):1639-1643
A number of naphthofuranones were synthesized and tested for COX-1 and COX-2 inhibition. Few of them were identified as selective COX-2 inhibitors. Structure-activity relationship studies within the series are discussed. 相似文献
13.
Afshin Zarghi Tannaz Zebardast Bahram Daraie Mehdi Hedayati 《Bioorganic & medicinal chemistry》2009,17(15):5369-5373
A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC50 = 0.05 μM) and selective (selectivity index = 259) COX-2 inhibitor. 相似文献
14.
Shannon D. Zanatta David T. Manallack Bevyn Jarrott Spencer J. Williams 《Bioorganic & medicinal chemistry letters》2009,19(2):459-461
3H-1,2-Dithiole-3-thiones substituted with a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) or a 3,5-di-tert-butyl-4-methoxyphenyl group at the C5 position were prepared and their ability to inhibit the cyclooxygenase isoenzymes, COX-1 and COX-2 was evaluated. Both compounds were potent inhibitors of COX-2 (relative to rofecoxib), and while the phenol was a weak inhibitor of COX-1, the methyl ether gave no measurable inhibition. Docking studies of the two compounds into the COX-1 and -2 active sites showed that the methyl ether could only fit in the COX-2 active site whereas the phenol could be docked into both COX-1 and -2. This study reports a new mode for inhibitor binding to COX-1 and -2 and a novel structural scaffold for the development of COX-2 selective inhibitors. 相似文献
15.
Serra S Ferino G Matos MJ Vázquez-Rodríguez S Delogu G Viña D Cadoni E Santana L Uriarte E 《Bioorganic & medicinal chemistry letters》2012,22(1):258-261
A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket. 相似文献
16.
Sano H Noguchi T Miyajima A Hashimoto Y Miyachi H 《Bioorganic & medicinal chemistry letters》2006,16(11):3068-3072
Indole- and indoline-type basic COX-1-selective competitive inhibitors, 5-amino-1-(3,5-dimethylbenzoyl)-1H-indole (1) and 5-amino-1-(3,5-dimethylphenyl)-2,3-dihydro-1H-indole (2), were found to possess anti-angiogenic activity estimated as a tube formation-inhibition using human umbilical vein endothelial cells (HUVECs). 相似文献
17.
Songarsa S Rajviroongit S Sae-Tang D Hannongbua S Kirtikara K Kittakoop P 《化学与生物多样性》2005,2(12):1635-1647
Racemosol (1) and 10-O-demethylracemosol (2), natural products from Bauhinia malabarica Roxb., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure-activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, two, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a-q were found to be critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table 1), its diacetoxy congener 3i was slightly more selective toward COX-2. In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table 2). 相似文献
18.
Pyridazinones as selective cyclooxygenase-2 inhibitors 总被引:4,自引:0,他引:4
Li CS Brideau C Chan CC Savoie C Claveau D Charleson S Gordon R Greig G Gauthier JY Lau CK Riendeau D Thérien M Wong E Prasit P 《Bioorganic & medicinal chemistry letters》2003,13(4):597-600
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained. 相似文献
19.
Scholz M Blobaum AL Marnett LJ Hey-Hawkins E 《Bioorganic & medicinal chemistry》2011,19(10):3242-3248
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological activities by inhibiting cyclooxygenase (COX)-1 and COX-2. Previous studies have shown that esters and amides of non-selective inhibitors such as indomethacin are selective against COX-2, which is the therapeutically relevant isoform. Structure-activity analysis indicates that substituted phenyl rings are tolerated as ester components. In the present study, the introduction of inorganic ortho- and meta-carbaborane moieties was explored with the aim to create COX-2 inhibitors and more importantly to investigate the validity of using these boron clusters as drug entities. Interestingly, only the ortho-carbaborane ester was active whereas the meta isomer was not. A similar lack of inhibitory potency was observed when an adamantyl substituent or alkylene spacers at the carbaborane were introduced in the ester functionality. 相似文献
20.
Abdur Rahim M Praveen Rao PN Bhardwaj A Kaur J Huang Z Knaus EE 《Bioorganic & medicinal chemistry letters》2011,21(20):6074-6080
A group of celecoxib analogs having a SO(2)NH(2) (9a-f), or SO(2)Me (12a-f), COX-2 pharmacophore at the para-position of the N-1 phenyl ring in conjunction with a C-5 phenyl ring having a variety of substituents (4-, 3-, 2-OAc; 4-Me,2-OAc, 4-Me,3-OAc, 4-F,2-OAc) was synthesized for evaluation as cyclooxygenase (COX) inhibitors of the COX-1/COX-2 isozymes. Within this group of compounds, 1-(4-aminosulfonylphenyl)-3-trifluoromethyl-5-(2-acetoxy-4-fluorophenyl)pyrazole (9f) emerged as the most potent (COX-1 IC(50)=0.7 μM; COX-2 IC(50)=0.015 μM) and selective (COX-2 selectivity index=47) inhibitor agent that exhibited good anti-inflammatory activity (ED(50)=42.3mg/kg) which was lower than the reference drug celecoxib (ED(50)=10.8 mg/kg), but greater than ibuprofen (ED(50)=67.4 mg/kg) and aspirin (ED(50)=128.7 mg/kg). Molecular modeling studies for 9f showed that the SO(2)NH(2) group assumes a position within the secondary pocket of the COX-2 active site wherein the SO(2)NH(2) oxygen atom is hydrogen bonded to the H90 residue (2.90?), the SO(2)NH(2) nitrogen atom forms a hydrogen bond with L352 (N?O=2.80?), and the acetyl group is positioned in the vicinity of the S530 residue where the acetyl oxygen atom undergoes hydrogen bonding to L531 (2.99?). 相似文献