The treatment of chronic inflammatory diseases represents an important clinic issue because of the side effects of the drugs commonly administered. The therapeutic regimen relies on the use of nonsteroidal antinflammatory drugs (NSAIDs), that act through the inhibition of cyclooxygenase enzymes (COXs), showing analgesic, antinflammatory and antipyretic properties. Two isoforms of COXs were identified: COX-1, which is constitutively expressed in all tissues, involved in homeostasis and gastrointestinal protection, and COX-2, mainly induced by inflammatory stimuli. Selective inhibitors of COX-2 (COXIBs) were developed. In spite of their reduced gastrotoxicity, COXIBs caused an increased cardiovascular risk of stroke and thrombotic lesions and were withdrawn from the market in 2005. An explanation for COXIBs cardiovascular toxicity can be found in the induction of an imbalance between the production of prostacycline (PGI2), vasodilator and platelet-aggregation inhibitor, and thromboxane (TXA2), vasoconstrictor and pro-aggregatory mediator. The design of new drugs able to inhibit COX-2 and to antagonize TXA2 is a new strategy to obtain new safer drugs for the treatment of chronic inflammatory diseases. In this work, a new series of COXIBs (20-34) was synthesized in order to extend our library of dual acting TXA2-antagonists/COX-2 inhibitors. The obtained compounds were tested in vitro to determine their ability to inhibit COX-1, COX-2 and the platelet aggregation mediated by TPα receptor activation. This work led to the identification of compound 23, that behaves as COX-2 inhibitor and TXA2 antagonist at submicromolar concentration, representing a good lead compound for the development of a new class of anti-inflammatory drugs.

PROGETTAZIONE E SINTESI DI NUOVI ANTAGONISTI DEL RECETTORE DEL TROMBOSSANO A2 /COX-2 INIBITORI: VERSO UNA TERAPIA PIÙ SICURA PER LE MALATTIE INFIAMMATORIE CRONICHE

MONTAGNA, SIMONE
2017/2018

Abstract

The treatment of chronic inflammatory diseases represents an important clinic issue because of the side effects of the drugs commonly administered. The therapeutic regimen relies on the use of nonsteroidal antinflammatory drugs (NSAIDs), that act through the inhibition of cyclooxygenase enzymes (COXs), showing analgesic, antinflammatory and antipyretic properties. Two isoforms of COXs were identified: COX-1, which is constitutively expressed in all tissues, involved in homeostasis and gastrointestinal protection, and COX-2, mainly induced by inflammatory stimuli. Selective inhibitors of COX-2 (COXIBs) were developed. In spite of their reduced gastrotoxicity, COXIBs caused an increased cardiovascular risk of stroke and thrombotic lesions and were withdrawn from the market in 2005. An explanation for COXIBs cardiovascular toxicity can be found in the induction of an imbalance between the production of prostacycline (PGI2), vasodilator and platelet-aggregation inhibitor, and thromboxane (TXA2), vasoconstrictor and pro-aggregatory mediator. The design of new drugs able to inhibit COX-2 and to antagonize TXA2 is a new strategy to obtain new safer drugs for the treatment of chronic inflammatory diseases. In this work, a new series of COXIBs (20-34) was synthesized in order to extend our library of dual acting TXA2-antagonists/COX-2 inhibitors. The obtained compounds were tested in vitro to determine their ability to inhibit COX-1, COX-2 and the platelet aggregation mediated by TPα receptor activation. This work led to the identification of compound 23, that behaves as COX-2 inhibitor and TXA2 antagonist at submicromolar concentration, representing a good lead compound for the development of a new class of anti-inflammatory drugs.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14240/36916