Cyclooxygenase inhibitors, development

Tenidap (Figure 8.26) is a dual cyclooxygenase (COX) and 5-lipoxygenase (5-LPO) inhibitor developed as an anti-inflammatory agent. Severe abnormalities in hepatic function were reported in Japanese clinical trials [28]. Although the thiophene is not directly implicated in these findings, the ready activation of this system to potential reactive metabolites may be suggestive of the involvement of this function. 

Many cyclooxygenase inhibitors have been developed and their structures are quite varied (Figure 32-3). All known inhibitors compete with fatty-acid... 

Inhibits mevalonic acid production and blocks the isoprenylation and membrane localization of Ras-family oncoproteins and nuclear lamins. Cyclooxygenase inhibitor. Inhibits the development and induces regression of premalignant adenomatous polyps. 

The discovery of how aspirin works has inspired medicinal chemists to search for new cyclooxygenase inhibitors that might behave as painkillers.f Celebrex is a recently developed prescription drug now sold for this purpose. 

The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. 

Komhoff, M., Wang, J. L., Cheng, FI. F., Langenbach, R., McKanna, J. A., Flarris, R. C., Breyer, M. D. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development, Kidney Int. 2000, 57, 414-422. 

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