STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH

Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.Based on these considerations, the aim of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs. The 3-carboxamide coumarins (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated

Mass spectrometry in the therapeutic drug monitoring of direct oral anticoagulants. Useful or useless?

Direct oral anticoagulants (DOACs) are now widely used in various thromboembolic diseases. Although routine therapeutic drug monitoring is not required, cumulative evidence suggests the usefulness of point measurement in some situations. Mass spectrometry is highly sensitive and specific and is considered the gold standard for the accurate measurement of DOAC plasma concentrations. However, lack of 24/7 availability, labour-intensive sample preparation and slow turn-around time of the analysis reduce its usefulness in emergency situations. Several coagulation or chromogenic assays have been introduced to estimate the plasma concentration of DOACs. In daily practice, these assays are recommended in most cases since they provide sufficient agreement with mass spectrometry over a broad range of concentrations. However, the assays are not perfect, and improvements are required to increase their sensitivity and/or specificity. This article focuses on the pros and the cons of mass spectrometry and specific coagulation/chromogenic assays

Thiosemicarbazide, a fragment with promising indolamine-2,3-dioxygenase (IDO) inhibition properties

With the aim to explore the interest of the thiosemicarbazide scaffold for the inhibition of the indoleamine 2,3-dioxygenase (IDO), a promising therapeutic target for anticancer immunotherapy, a series of 32 phenylthiosemicarbazide derivatives was prepared and their IDO inhibition evaluated. Our study demonstrated that among these derivatives, compound 14 characterized with a 4-cyanophenyl group on the thiosemicarbazide was the more potent IDO inhibitor in this series being endowed with an IC50 of 1.2 μM. The SAR depicted showed that substitution in the 3- and 4-position relative to the phenylthiosemicarbazide are very promising whereas substitution in the 2-position always leads to less potent or inactive derivatives. In fact the study highlighted a novel interesting scaffold for IDO inhibition for further development