Anti-thrombotic Therapies: Targeting Novel Approaches to Improve the Treatment of Cardiovascular Disease
Abstract
Cardiovascular disease is the leading cause of death globally. Platelets are a well-established target in the treatment of thrombosis; however, current therapies continue to target a core group of proteins in the platelet, and many patients remain at risk for cardiovascular events. As a result, the development of novel anti-thrombotic therapeutics remains an important goal in the cardiovascular field. This dissertation focuses on three novel anti-thrombotic mechanisms and their potential as therapeutic agents. CS585, a novel prostacyclin receptor (IP) agonist, targets a well-known inhibitory pathway in the platelet that has had limited success with pharmacological intervention in the past. Sotagliflozin, a sodium-glucose cotransporter (SGLT)1/2 inhibitor developed to treat diabetes, has been observed to decrease cardiovascular risk and demonstrates an inhibitory effect on platelet activity. CS014, a novel histone deacetylase (HDAC) inhibitor, reduces thrombus formation in vivo. The work outlined in this dissertation sought to assess the viability of the three compounds as potential anti-thrombotic therapeutics. We evaluated the effects of CS585, sotagliflozin, and CS014 on platelet activation and thrombus formation in numerous in vivo and ex vivo models of thrombosis. Additionally, each compound was evaluated for a potential impact on hemostasis, a key limitation of many anti-thrombotic medications. CS585 was developed as an analogue of the omega-6 polyunsaturated fatty acid…
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