Design and Synthesis of Phenylguanidine-Based and Benzamidine-Based FXIIa Inhibitors

Student thesis: Doc typesDoctor of Sciences

Abstract

The Coagulation Factor XIIa has emerged as a potential therapeutic target for a whole range of medical conditions, including thrombosis, Alzheimer’s disease, sepsis, and multiple sclerosis. Despite their upsides compared to biological or biobased inhibitors, research for synthetic small inhibitors of FXIIa is scarce. Consequently, the in vivo non-clinical and clinical development of this category of compounds is close to non-existent compared to its alternatives. In an attempt to fill this gap, the general aim of this thesis was to design and to synthesize small, non-peptidic molecules targeting FXIIa in order to generate hit compounds that could be used to identify promising scaffolds and to yield lead compounds.

In the first part of this thesis, we focused on the structural refinement of 2,5-dichlorobenzyl triazole inhibitors. The adequacy of the envisaged modulations was first highlighted using molecular docking. The promising compounds were then synthesized and tested in vitro on FXIIf to assess their potency. The analysis of the results allowed us to further refine the structure of the potential inhibitors, using once again molecular docking, in an iterative process.

In the second part of this thesis, in an attempt to develop new tools to simplify and to increase the throughput of our syntheses, we investigated a novel methodology of early-stage amidination, leading to fully Boc-protected amidine compounds. In order to make this synthetic strategy as versatile as possible, the compatibility of such intermediates with some of the most used reactions in medicinal chemistry, namely Pd-catalyzed cross couplings and substitution reactions, was verified experimentally.

In parallel to this work, our group tested numerous compounds from our in-house chemolibrary and two potent biscationic compounds were identified: nafamostat and pentamidine. In the third part of this thesis, three derivatives of these compounds will be designed using molecular docking in order to improve their potency, their selectivity and their metabolic stability, in an attempt to make them more suitable as potential lead compounds. Their synthesis will then be tackled using our improved early-stage amidination metholodogy.
Date of Award18 Dec 2020
Original languageEnglish
Awarding Institution
  • University of Namur
SupervisorSTEVE LANNERS (Supervisor), Lionel POCHET (Co-Supervisor), Guillaume Berionni (President), Raphaël Frédérick (Jury), Jean-Pierre Gillet (Jury), Raphaël Robiette (Jury) & Wim M. De Borggraeve (Jury)

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