New Cyclooxygenase-2/5-Lipoxygenase Inhibitors. 3. 7-<i>tert</i>-Butyl-2,3-dihydro-3,3-dimethylbenzofuran Derivatives as Gastrointestinal Safe Antiinflammatory and Analgesic Agents:  Variations at the 5 Position

Janusz, John M.; Young, P. A.; Ridgeway, J. M.; Scherz, Michael W.; Enzweiler, K.; Wu, Laurence I.; Gan, Lin; Chen, J.; Kellstein, David; Green, S. A.; Tulich, J. L.; Rosario-Jansen, Theresa; Magrisso, I. Jack; Wehmeyer, Kenneth R.; Kuhlenbeck, Debra L.; Eichhold, Thomas H.; Dobson, Roy L. M.

doi:10.1021/jm9802416

Cited by 49 publications

(25 citation statements)

References 24 publications

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“…The conclusion of these investigations is that no structure appeared pharmacologically superior to the DHDMBF structure [170]. Finally, several other functional groups have been introduced at the 5-position of the DHDMBF ring: amides, amidines, ureas, guanidines, amines, heterocycles, heteroatomics and heteroaryl ethenyl substituents and all provided active compounds [171]. Examples of such compounds are given in Fig.…”

Section: Nhmentioning

confidence: 99%

New Trends in Dual 5-LOX / COX Inhibition

Leval¹,

Julémont²,

Delarge³

et al. 2002

CMC

109

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Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. The interest of developing such compounds is supported by a large number of pharmacological studies. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activity. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of COX inhibitors. The mechanism of their gastric-sparing properties is not completely understood, although it has been demonstrated that leukotrienes significantly contribute to the gastric epithelial injury. Finally, both COX and LOX derivatives (prostanoids and leukotrienes, respectively) are involved in other diseases than inflammation such as cancer proliferation where the use of dual inhibitors could be an interesting approach.

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Section: Nhmentioning

confidence: 99%

New Trends in Dual 5-LOX / COX Inhibition

Leval¹,

Julémont²,

Delarge³

et al. 2002

CMC

109

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“…There are two strategies for this combination: developing dual functional COX-2 and 5-LOX inhibitors, or using a mixture of these two types of inhibitors. A few papers have been published on the development of these two anti-inflammatory strategies, and some drug candidates have already been in clinical tests [26][27][28][29][30][31]. When using a combination of inhibitors, two issues need to be considered: one is the mixing ratio (MR) of different single-functional inhibitors, which makes great contributions to the efficacy and safety of the mixture; the other is the relative inhibition constant to different enzymes (DR), which decides the therapeutic effect of the dual-functional inhibitor.…”

Section: Author Summarymentioning

confidence: 99%

Dynamic simulations on the Arachidonic Acid Metabolic Network

Yang¹,

Ma²,

Liang³

et al. 2005

PLoS Comput Biol

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Drug molecules not only interact with specific targets, but also alter the state and function of the associated biological network. How to design drugs and evaluate their functions at the systems level becomes a key issue in highly efficient and low-side-effect drug design. The arachidonic acid metabolic network is the network that produces inflammatory mediators, in which several enzymes, including cyclooxygenase-2 (COX-2), have been used as targets for antiinflammatory drugs. However, neither the century-old nonsteriodal anti-inflammatory drugs nor the recently revocatory Vioxx have provided completely successful anti-inflammatory treatment. To gain more insights into the anti-inflammatory drug design, the authors have studied the dynamic properties of arachidonic acid (AA) metabolic network in human polymorphous leukocytes. Metabolic flux, exogenous AA effects, and drug efficacy have been analyzed using ordinary differential equations. The flux balance in the AA network was found to be important for efficient and safe drug design. When only the 5-lipoxygenase (5-LOX) inhibitor was used, the flux of the COX-2 pathway was increased significantly, showing that a single functional inhibitor cannot effectively control the production of inflammatory mediators. When both COX-2 and 5-LOX were blocked, the production of inflammatory mediators could be completely shut off. The authors have also investigated the differences between a dual-functional COX-2 and 5-LOX inhibitor and a mixture of these two types of inhibitors. Their work provides an example for the integration of systems biology and drug discovery.

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“…Tepoxalin underwent clinical evaluation for psoriasis and rheumatoid arthritis but unfortunately was discontinued in Phase II [114]. A COX/5-LO inhibitor currently evaluated in clinical trials for arthritis is S-2474, which displays excellent anti-inflammatory and analgesic activities associated with remarkable gastric safety [115,116]. RWJ-63556, a compound structurally related to the selective COX-2 inhibitor nimesulide, is another potent orally active COX-2/5-LO inhibitor with remarkable antiinflammatory activity in experimental carrageenan-induced inflammation [117].…”

Section: -Lo Inhibitors That Directly Block the Enzyme´s Activitymentioning

confidence: 99%