Structure activity relationship of cox 2 inhibitors

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

structure activity relationship of cox 2 inhibitors

A plethora of selective COX-2 inhibitors belonging to nine chemical classes subjected to quantitative structure-activity relationship (QSAR) analysis using. In conclusion, a second wave of COX-2 inhibitors with higher biochemical Screening and structure-activity relationship studies have been performed in order. One compound 7c showed more potent anti-inflammatory activity than COX-II inhibitor: Design, synthesis and structure-activity relationship.

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships - Semantic Scholar

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Gastrointestinal effects of non-steroidal anti-inflammatory drugs. Profile and mechanisms of gastrointestinal and other side effects of non-steroidal anti-inflammatory drugs NSAIDs. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other non-steroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs.

Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Hinz B, Brune K. Oxford Textbook of Rheumatology. Oxford University Press; Testa B, Kier LB.

Quantitative Structure-Activity Relationship (QSAR) Study of Cyclooxygenase-2 (COX-2) Inhibitors

The concept of molecular structure in structure-activity relationship studies and drug design. Application of topological and physicochemical descriptors: These computed parameters were correlated with experimental inhibitory activities pIC Multilinear regression analyses produced three statistically acceptable models. Model 1 is based on quantum mechanical properties only, Model 2 is an all-E-state relationship, and Model 3 embraces both quantum mechanical and electrotopological parameters.

structure activity relationship of cox 2 inhibitors

All three models surpassed the commonly allowed minimum predictive squared correlation coefficient q2 of 0. These QSAR results and the probable pharmacophore features identified in this study offer important structural insight into designing novel anti-inflammatory drugs devoid of unwelcome side effects. Guided by the generated models, 18 chemical structures belonging to spiroalkene classes were designed with calculated pIC50 values higher than that of known potent COX-2 inhibitors.

Nonsteroidal anti-inflammatory drugs NSAIDs are profoundly used in the treatment of wide variety of inflammatory conditions including osteoarthritis and rheumatoid arthritis Vane et al. However, these drugs are associated with high risk of gastrointestinal and renal adverse effects Allison ; DeWitt ; Deviere NSAIDs act by inhibition of cyclooxygenase COXthe enzyme involved in the biosynthesis of prostaglandins, prostacyclins and thromboxanes from arachidonic acid Dannhardt ; Bleumink Gastrointestinal damage associated with the use of nonsteroidal antiinflamatory drugs.

N Engl J Med Non-steroidal antiinflammatory drugs and heart failure. Validation of the general purpose tripos 5.

structure activity relationship of cox 2 inhibitors

A Comparative Molecular Field Analysis. J Med Chem This kDa multidrug resis- chemotherapy-induced resistance in human tumours is tance-associated protein mediates the ATP driven uni- therefore an important challenge [1]. These proteins belong to the adenosine tri- tion with leukotriene C4 LTC4 binding site s [4,8]. S 02 S. Both analogue number and chemical nomenclature are given for each compound Compound Mol. Evi- synthesised and screened to further investigate the dence suggests that the gastrointestinal toxicity structure—activity relationship SAR of indomethacin- associated with NSAID use is primarily the result of mediated MRP inhibition Table 1 [21].

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The expres- sion of COX-2 in a number of cancer types, including 2. COX-2 is also 2.

  • Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships
  • Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships.

VP and vincristine in vitro when co-administered in cell lines which express MRP These results are con- 2. Chemicals sistent with other published data [18,19]. The indo- ml. All compounds synthesised were fully char- before being applied to 0.

Quantitative Structure-Activity Relationship Study of COX-2 Inhibitors

In control experiments, ATP was replaced was measured by colormetric assays as previously with adenosine monophosphate AMP to determine the described [17,22,23]. All assays were performed in triplicate. Preparation of inside-out vesicles from plasma Jakoby [25]. The homogenate drug were added. The diluted homo- with PBS.

structure activity relationship of cox 2 inhibitors

The pellets were resus- 2. Vesicle transport assay using LTC4 2. The tubes were mixed for 10 S. Samples were then analysed using the minute r. Concentrations of the dichloromethane phase bottom phase and added PGE2 present in the samples were determined from a to the HPLC autosampler vials.

The vial contents were standard curve of absorbance at nm versus PGE2 evaporated under nitrogen and resuspended in 50 ml of concentration.

Measurement of the test samples by HPLC was carried out as previously described in 2. Statistical analysis of combination toxicity assays Refs. Results obtained from the analysis of data using the 2. The The spectrophotometric assay, for measuring COX-1 program provides combination index CI values which activity, has been previously described in Refs. The reaction was terminated The combination toxicity assay was the preliminary by the addition of trichloroacetic acid.

Enzyme activity biological assay carried out on the compounds to assess was measured by the thiobarbituric colour reaction of if the analogues of indomethacin at non-toxic con- malonaldehyde formed in the reaction and determined centrations were capable of potentiating the toxicity of by a spectrophotometer at nm.

DLKP cells were used in the combination toxicity assay as this cell 2. A number of N-benzyl logues. Cells were seeded at high density 2. In the per well in 6 well plates. The cell line, A, a human combination toxicity assays, the potentiation activity lung adenocarcinoma, was chosen for the experiment as was maintained after removing the carbonyl group it was demonstrated by Asano and colleagues [29], that alone from the indomethacin structure 4.

But when leukin-1b IL-1b. The plates were incubated overnight this chlorine was replaced with a methylthio substituent in serum-containing media. The media was removed 5 the compound was rendered inactive. Moving after this incubation and washed twice with fresh media. Analogue 18 proved to be the only exception to the cells. Control wells were treated with media only.

All combi- 22 5 0. Data are expressed as combination index tive in this assay. CI values for the combination as described in the Materials and A number of the analogues, active in the combination Methods. All combination data were obtained from triplicate deter- toxicity assay in DLKP cells, were analysed in combi- minations.