Design, synthesis and evaluation of coagulation FXIIa, inhibitors as potential antithrombotic agents

Promoter

Dr. Lionel POCHET, UNamur, Department of Pharmacy

Jury

Membres du jury extérieur : Prof. Christian CHATELAIN, CHU UCL Namur site de Godinne ; Prof. Pascal DE TULLIO, Université Liège  ;  Prof. Hugo TEN CATE, Maastricht University Medical Center.

Membres du jury intérieur : Jean-Michel DOGNE, Faculté Médecine, Département Pharmacie ; Lionel POCHET, Faculté Médecine, Dpt Pharmacie ; Prof. Steve LANNERS, Faculté Sciences, Laboratoire Chimie organique de synthèse ; Prof. Bernard MASEREEL, Faculté de Médecine, Département Pharmacie.

Summary

The Holy Grail of anticoagulation is to tackle thrombosis without causing bleeding in patients. The direct oral anticoagulants come closer to this goal but bleeding is still reported. That is why research efforts are currently focusing on targets acting upstream in the coagulation cascade. One of these is factor XIIa (FXIIa), a serine protease involved in the contact pathway. Based on numerous animal studies, it appears that the inhibition of this clotting factor would finally offer protection against thrombosis without impairing hemostasis. Also, the inhibition of FXIIa could open new clinical perspectives including the safe prevention of medical devicerelated thrombosis. To date, the FXII(a) inhibitors under development include proteins, peptides, RNA-based inhibitors and antibodies. In contrast, smallmolecular-weight inhibitors are rather left behind.

Given the FXIIa inhibitors landscape, the objective of this thesis was to design, synthesize and assess small molecules able to inhibit FXIIa.

The project started with pharmacomodulations of 3-carboxamido coumarins. Inhibitors with a micromolar activity were obtained and the building of an original 3D model of FXIIa allowed to better explore the activity and selectivity of the best coumarin in the series. In a second study, we wanted to provide novel FXIIa inhibitors. For that purpose, we used a strategy deriving from the fragment-based drug design (FBDD). This work afforded several 2,5-dichlorobenzyl-triazole derivatives having a micromolar activity on FXIIa. The design of these lipophilic molecules was guided by the need to develop oral drugs since this delivery mode is not achievable with the inhibitors under development. Unfortunately, these molecules are more complex to study. We thus decided to devote the last part of the thesis to the investigation of soluble compounds. Indeed, small soluble molecules are easier to assess and are clinically interesting. At the end of this study, we found a small contact inhibitor able to interfere with the clot formation in plasma and blood.

Ultimately, this project brings an additional stone in the development of organic small FXIIa inhibitors and it could serve for future medicinal chemistry projects.