Selective COX-1 Inhibition: A Therapeutic Target to be Reconsidered

M.      G. Perrone; A.      Scilimati; L.      Simone; P.      Vitale

Abstract

Since cyclooxygenase (COX) isozymes discovery, many papers and reviews have been published to describe the structural bases of COX inhibition, and to debate on the therapeutic and adverse effects of worldwide clinically used nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective inhibitors (well known as Coxibs). COX-2 inhibition has been widely investigated, whereas the role of COX-1 in human pathophysiology is mostly not yet well ascertained. As time goes on, the cliche that the constitutively expressed isoform COX-1 is only involved in normal physiological functions, such as platelet aggregation, gastric mucosa protection and renal electrolyte homeostasis is going to be shattered. Low-dose aspirin, behaving as a preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by this isoenzyme in many mammalian cell types. This review would elucidate the most recent findings on selective COX-1 inhibition and their relevance to human pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain. It would also focus on the design and development of new highly selective COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a deeper insight of the role of COX-1 in human health and disease. Among the traditional NSAIDs, other then aspirin and indomethacin, only few examples of selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have been so far identified. This review has also the scope to stimulate the development of novel drugs, which activity is COX-1 mediated.

Keywords: Cyclooxygenase, selective inhibitors, structure-activity relationships, cyclooxygenase (COX), isozymes, nonsteroidal anti-inflammatory drugs, renal electrolyte, homeostasis, aspirin, COX-1 inhibition, neuro-inflammation, mofezolac, arachidonic acid, prostanoids, acetaminophen, prostaglandin, housekeeping gene, lipopolysaccha-ride, interleukin, tumor necrosis factor, phorbol myristate acetate, atherosclerotic plaque, thromboxane, hydroperoxide, Nephrotoxic syndromes, lipopolysaccharide, tumorigenicity, adenocarcinoma, neoplasias, prostacyclin, atherothrombosis, mutagenesis, neurodegenerative disorders, neuroinflammation, microglia, Alzheimer's disease (AD), hippocampus, indomethacin, Parkinson's disease (PD), traumatic brain injury, Creutzfeldt-Jacob disease, blood-brain barrier (BBB), epileptogenesis, celecoxib, rofecoxib, Neuropathic pain, nociceptors, leptomeninges, ventromedial preoptic nucleus (VMPO), ventrolateral medulla (VLM), tumorigenesis, po-larographic oxygen electrode, enzyme immunoassay, radioimmunological assay, Salicylic acid, Pyrazolones, Dipyrone, Oxicams, Diarylheterocycles, Benzenesulfonanilide, Arylpropionic Acids, Stilbenes, Curcumin, Sulindac Derivatives