COX‐1 Inhibitors: Beyond Structure Toward Therapy

Abstract

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

“…Among the FDA-approved NSAIDs, ketorolac preferentially inhibits COX-1 and exhibits lower COX-2 activity (57, 58). To determine whether the observed antitumor activity of preoperative ketorolac was mediated by COX-1 and/or COX-2 inhibition, we utilized 3 highly selective COX-1 inhibitors (SC-560, FR122047, or TFAP), the selective COX-2 inhibitor celecoxib, and the nonselective COX inhibitor indomethacin (38,59). Similar to ketorolac, preoperative administration of the selective COX-1 inhibitors resulted in long-term survival in 40%-50% of mice up to 230 days after LLC resection (Figure 2A).…”

Study of the Inhibitory Effects of Enteral Nutrition Formula on Indomethacin-Induced Gastric Lesions in Mice

“…These drugs, however, also cause NSAID-induced ulcers by inhibiting the gastric mucosal protective effects of PG [1,2], characteristically producing relatively shallow ulcers predominantly in the pyloric antrum [3]. Since recent studies show that NSAID-induced ulcer is caused by the simultaneous inhibition of both COX-1 and COX-2, efforts have been continued to develop new COX inhibitors with selectivity for either COX-1 or COX-2 [4,5]. Although such selective inhibitors are less likely to cause the undesirable gastrointestinal side effects, most of the currently available NSAIDs exhibit gastrointestinal mucosal damage as a common adverse reaction.…”

Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship

“…12‐LO catalyzes the stereo‐specific peroxidation of polyunsaturated fatty acids generating the bioactive lipid mediator (12S)‐HPETE which regulates several biological processes including platelet activation and angiogenesis. COX‐1 catalyzes the biosynthesis of prostaglandins which have several important physiological roles including the control of gastric secretions and nociception.…”