Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the treatme nt of inflammatory disease and are among the most widely used drugs worldwi de. They are anti-inflammatory, antipyretic, and analgesic and are prescrib ed as first choice for the treatment of rheumatic disorders and, in general , inflammation. The main limitation in using NSAIDs consists in their side- effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of c yclooxygenase (COX), and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects o f NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible i soform). Arachidonic acid can also be converted to leukotrienes (LTs) by th e action of 5-lipoxygenase (5-LOX). LTC4, LTD4, and LTE4 are potent broncho constrictors, whereas LTB4 is chemotactic for leukocytes and plays an impor tant role in the development of gastrointestinal ulcers by contributing to the inflammatory process. Thus, developing dual inhibitor compounds that wi ll simultaneously inhibit COX and 5-LOX could enhance their individual anti -inflammatory effects and reduce the undesirable side-effects associated wi th NSAIDs, especially of the gastrointestinal tract. The most promising COX /5-LOX inhibitor is ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-d ihydro-1H-pyrrolizine-5 -yl]-acetic acid), now in Phase III clinical trials . This new approach will certainly help to unravel the mechanisms at the ro ot of the undesirable effects of NSAIDs and to develop safer NSAIDs. (C) 20 01 Elsevier Science Inc. All rights reserved.