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. COX-2 inhibitors have been successful in treating inflammatory diseases like acute pain, rheumatoid arthritis and osteoarthritis; a few of them are also being studied for treating different types of cancer and Alzheimer's disease (1). Despite a few recent cautionary reports, the coxib treatment has a high degree of benefit over risk, and strategies for using NSAIDs have been described by Antman et al. (2). A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl--1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti--inflammatory activity by the rat paw edema method. p--Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4--methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L -1 and COX-1 enzyme inhibition of 44% at 88 mmol L -1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L -1 ) and higher COX-1 enzyme inhibition (53% at 88 µmol L -1 ) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg -1 ) vs. celecoxib (48% at 12.5 mg kg -1 ). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

This article presents in brief the development of farnesyltransferase inhibitors (FTIs) and their preclinical and clinical status. In this review the mechanism of action of FTIs is discussed and their selectivity issue towards tumor cells is also addressed. The significant efficacy of FTIs as single or combined agents in preclinical studies stands in contrast with only moderate effects in Clinical Phase II-III studies. This suggests that there is a need to further explore and understand the complex mechanism of action of FTIs and their interaction with cytotoxic agents.