A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors

Li, Chun‐Sing; Black, W. Cameron; Brideau, Christine; Chan, Chi Chung; Cromlish, Wanda; Claveau, David; Gauthier, Jacques Yves; Greig, Gillian; Grimm, Erich L.; Guay, Jocelyne; Lau, Cheuk K.; Riendeau, Denis; Thérien, Michel; Visco, Denise M.; Wong, Elizabeth; Xu, Lijing; Prasit, Petpiboon

doi:10.1016/s0960-894x(99)00559-4

Cited by 30 publications

(14 citation statements)

References 10 publications

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“…were initiated at the designated time (either 10 min before or 2 or 6 h after injury) and continued for 3 days after injury. Dosages corresponded to effective doses given in systemic inflammation models (15,48) and were arrived at in consultation with Dr. Jilly Evans (Merck). The drug was suspended in 5% poly-ethoxylated vegetable oil (Emulphor; GAF Corp., New York, NY) in saline by mixing vigorously for 30 seconds at room temperature with a rotor-stator device.…”

Section: Drug Dosingmentioning

confidence: 99%

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Gopez¹,

Yue²,

Vasudevan³

et al. 2005

Neurosurgery

104

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OBJECTIVE-Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2( 5 H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. METHODS-DFU NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript RESULTS-DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E 2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injuryinduced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain.CONCLUSION-These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.Keywords 2-Arachidonoyl glycerol; Caspase-3; COX2 inhibitor; Eicosanoids; Endocannabinoid; Neuroinflammation; Rat behavior Traumatic brain injury (TBI) initiates a central inflammatory response that results in the increased production of prostaglandins and reactive oxygen species. These products may cause secondary insults to the brain (55,90,94). Cyclooxygenases catalyze the first step in the formation of prostaglandins from arachidonic acid, producing reactive oxygen species in the process. Cyclooxygenase-1 (COX1), present normally in most tissues, is thought to maintain essential physiological functions, such as gastric mucosal integrity, renal function, and platelet homeostasis (87,101). COX2, the inducible isoform, is expressed in the normal brain (30,87) but is rare or absent in most organs under normal conditions. As in the periphery (32,79), COX2 in the brain can be regulated by inflammatory cytokines (87), and prostaglandin production increases in response to pathological conditions of the central nervous system (3,70,72,89,107). ...

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Section: Drug Dosingmentioning

confidence: 99%

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Gopez¹,

Yue²,

Vasudevan³

et al. 2005

Neurosurgery

104

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“…More analogues of 6, obtained by replacing the isopropoxy group with phenyl /substituted phenyl and replacing oxygen of the alkoxy group with S, NH, CO, CH 2 , have been investigated for COX-2 inhibition [16]. Among these compounds, 7 and 8 (Chart 3) have been identified as the highly potent but less selective than 6 towards COX-2.…”

Section: O-containing 5-membered Heterocyclesmentioning

confidence: 99%

Current Status of COX-2 Inhibitors

Singh¹,

Mittal

2008

MRMC

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The two isoforms of enzyme cyclooxygenase viz. COX-1 and COX-2 play key roles in the metabolism of arachidonic acid. The enzyme COX-2, when over expressed, leads to more production of prostaglandins causing inflammation and it also participates in the propagation of cancer. Therefore, COX-2 becomes the cellular target of a number of chemical entities for the treatment of inflammatory diseases as well as for the chemotherapy of cancer. In the present review, an up to date status of the compounds investigated for COX-2 inhibition has been given so that a collective view of the existing COX-2 inhibitors could be helpful for the design of safer anti-inflammatory drugs. In order to cover the maximum reported COX-2 inhibitors, a unique classification on the basis of the central core of the molecule (carrying mostly the phenyl moieties) has been followed, an outline of which has been given below: [structure: see text]. Each category of compounds has been discussed with suitable examples giving the IC(50) (for COX-2) values and the selectivity towards COX-2 over COX-1 of most potent compounds.

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“…Conformational and electronic parameters were calculated for 79 inhibitors of COX-2 taken from different series [50][51][52][53][54][55][56]. Biological activities of these compounds were measured on human COX-2 (in the whole cell and/or whole blood assays) and, for some of them, correlated with measurements on the rat paw edema assay.…”

Section: Data Setsmentioning

confidence: 99%

The Structure - Inhibitory Activity Relationships Study in a Series of Cyclooxygenase-2 Inhibitors: A Combined Electronic-Topological and Neural Networks Approach

Димогло¹,

Kovalishyn

Shvets

et al. 2005

MRMC

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Structure-activity relationships study was performed for a few series of cyclooxygenase-2 (COX-2) inhibitors by using the Electronic-Topological Method combined with Neural Networks (ETM-NN). Specific molecular fragments were found for active compounds ('activity features') from both series by the ETM application. After this, a system of prognosis was developed as the result of training Kohonen's self-organizing maps (SOM) by the fragments. From the detailed analysis of all compounds under study, requirements necessary for a compound to be COX-2 inhibitor were formulated. The analysis showed that any requirements violation for a molecule resulted in a considerable decrease or even complete loss of its activity. The found activity features identified correctly different marketed drugs and new compounds that had passed pre-clinical and clinical trials; this fact confirms the workability of the system developed for the COX-2 inhibitory activity prediction.

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A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors

Cited by 30 publications

References 10 publications

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Current Status of COX-2 Inhibitors

The Structure - Inhibitory Activity Relationships Study in a Series of Cyclooxygenase-2 Inhibitors: A Combined Electronic-Topological and Neural Networks Approach

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