Using fragment-based lead discovery to generate new scaffolds for the development of FXIIa inhibitors

Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. Up to now, the direct oral anticoagulants (DOACs) on the market induce severe bleeding side effects. One of the strategies in the search for safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa). Studies with different animal models suggest that the inhibition of FXII or FXIIa is an opportunity to develop anticoagulants devoid of a bleeding risk associated with anti-inflammatory properties. In addition, anti-FXII directed therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting medical devices [1]. Besides this advantage in the field of thrombosis, the FXIIa inhibition also rises as a therapeutic strategy to interfere with excessive vascular leakage in patients suffering from hereditary angioedema [2] and as an emerging research field in neuro-inflammatory and neurodegenerative disorders [3].

The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans [4]. Encouraging results demonstrate that the compounds are anticoagulants and are quite selective for the contact phase pathway [4c]. Importantly, this study showed that aromatic guanidine is an attractive starting point in the design of FXIIa inhibitors. Besides the modulations of the 3-carboxamide coumarins, the search for new chemical scaffolds has been started. To facilitate chemical exploration, we decided to apply a fragment-based lead discovery approach (FBLD).

With this aim in view, we set up a high concentration bioassay as primary screening and we elaborate an initial library of fragments bearing an amidine or a guanidine moiety. The library was further enlarged with available in-house compounds and with structures close to potent serine protease inhibitors described in the literature. For the constitution of this library, computational studies were also undertaken.

[1] a) A.H. Schmaier, E.X. Stavrou, Res Pract Thromb Haemost. (2019), 1–8.; b) B. Tillman, D. Gailani, Semin Thromb Hemost. (2018), 44(1), 60–9.
[2] J. Bjorkqvist, S. de Maat, U. Lewandrowski, A. Di Gennaro, C. Oschatz, K. Schonig, M.M. Nothen, C. Drouet, H. Braley, M.W. Nolte, A. Sickmann, C. Panousis, C. Maas, T. Renne, J Clin Invest, 125 (2015) 3132-3146.
[3] S. Lorenzano, M. Inglese, T. Koudriavtseva, Editorial: Role of Coagulation Pathways in Neurological Diseases. Front Neurol (2019), 10, 1–3.
[4] a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194; c) C. Bouckaert , S. Zhu, J. W. P. Govers-Riemslag, M. Depoorter, S. L. Diamond, L. Pochet, Thromb Res, 157 (2017) 126-133.