Synthèse et utilisation de benzotriazepinones comme modulateur du système urotensinergique

Peptides are potentially interesting therapeutic agents, due to their low toxicity and excellent activity. They have however disadvantages, such as rapid metabolism, poor bioavailability and potential to react indiscriminately with multiple receptors, which may lead to secondary effects. To address such issues, modified peptide analogs, so-called peptidomimetics, have been developed.  One type of peptidomimetic consists of the complete replacement of the peptide structure by a small molecule that mimics the important backbone and side chain conformation and functions for activity. In addition, certain molecules, such as benzodiazepines have been described as privileged structures, because of their affinity for many peptide receptors. The aza-analogues, benzotriazepines, have received a lot less attention than the parent benzodiazepines, in part due to difficulties in their synthesis, necessitating toxic reagents, harsh reaction conditions, and multiple protecting groups to obtain compound in low yield.  The Urotensin II (UT) receptor is a member of the G protein-coupled receptor family, and interacts with two endogenous cyclic peptide ligands: urotensin II (hUII, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and the urotensin II-related peptide (URP, H-Ala-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH). The so-called urotensinergic system has among various physiological roles, significance in the pathogenesis and the progression of cardiovascular diseases. The conception of ligands which can differentiate the signaling and phenotypic outcomes of UII and URP are necessary to more effectively target UT for therapeutic development.  This thesis focuses on two principle objectives: the development of new methods for the synthesis of diverse 1,3,4-benzotriazepin-2-ones, and the application of the latter as peptidomimetics that modulate selectively the endogenous ligands of the urotensinergic system. An approach featuring chemo-selective alkylation of a semicarbazone intermediate has been developed to produce diverse benzotriazepin-2-ones. In addition, the achiral benzotriazepinones were shown to have potential to serve as peptide gamma-turn mimics.  The benzotriazepinone scaffold was employed to create achiral allosteric UT modulators by mimicry of the purported turn confirmation of the tripeptide sequence, Bip-Lys-Tyr, in the biologically active UT regulator Urocontrin ([Bip4]URP). A series of 27 compounds was synthesized by our method to study structure-activity relationships for UT modulation. Certain benzotriazepinones exhibited capacity to selectively modulate the effects of hUII and URP in ex vivo studies of rat aorta contraction.  To improve antagonist activity, a N-benzylamide was installed at the benzotriazepine 8-position to mimic the phenylalanine residue in Urocontrin. Moreover, photo-reactive analogs have been pursued by introduction of a benzophenone residue towards the goal of binding UT covalently to identify the location responsible for modulation of hUII and URP activity.  In conclusion, advances have been made in the synthesis and application of benzotriazepinones as peptide -turn mimics. Methods to diversify effectively the heterocycle have empowered development of achiral modulators of the UT receptor. Fundamental and applied advancements of knowledge have thus been made in the domains of peptide mimicry and medicinal chemistry.

Keyphrases: benzotriazepinone, chemoselective alkylation, peptide mimicry, UT modulator, urotensinergic system