COXTRANS: una nuova classe di inibitori duali delle ciclossigenasi e del recettore del trombossano

Due to the anti-inflammatory, analgesic and anti-pyretic actions, nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed drugs, which act through inhibition of the cyclooxygenases (COXs). COXs are enzymes that catalyze the conversion of arachidonic acid, a polyunsaturated fatty acid present in cell membranes, to prostaglandin PGH2, precursor of pro-inflammatory mediators including prostaglandins (PGs), prostacyclin (PGI) and thromboxanes (TXs). Two COX isozymes are present, COX-1 is constitutively expressed in most tissues, including kidney and gastric, and has housekeeping purpose, while COX-2 is highly regulated by inflammatory stimuli, but it is also constitutively expressed in brain, kidney and endothelial cells. NSAIDs encompass a large class of drugs, which do not inhibit COX-1 and COX-2 to the same extent. Selective COX-2 inhibitors (COXIB) were developed to selectively inhibit the action of COX-2 induced during the inflammatory processes. Unfortunately, increasing evidence for cardiovascular hazard associated with COXIB emerged, suggesting that selective inhibition of the COX-2, despite the efficacy and the gastrointestinal safety, could lead to undesired disruption of the intricate prostanoid network1. A potential strategy to mitigate the COXIB-associated cardiovascular effects could be targeting the TX receptor (TP) to balance the vasoconstrictor and pro-aggregatory action of TXA2 and the vasodilator and platelet antiaggregating effects of PGI2. Recent studies have shown that the use of NSAIDs may reduce the risk for Alzheimer’s Disease (AD). AD is a complex neurodegenerative disorder with multiple dysfunctional pathways, including the formation of amyloid-β (Aβ) plaques in brain and the loss of the blood-brain barrier (BBB) integrity and function. Recently has been demonstrated the involvement of COX-2 and TP activation for both these pathogenesis pathways2. The aim of this project is to obtain safer compounds in term of side effects and, in perspective of AD therapy, to act on more than one pathway involved in the pathogenesis of the disease. In this thesis, compounds 1-11 were synthesized in order to obtain a new class of drugs (COXTRANS) acting both as COX-2 inhibitors and TP antagonists. The synthesized compounds have been tested in in vitro and ex-vivo systems to evaluate their activity on both targets.