title: Synthesis of tailor-made bicyclic [4.3.1] aza-amides
Creators: name: Kolos, Jürgen
Publisher: name: UNSPECIFIED
Year: 2023

description: FK506-binding proteins (FKBPs) have emerged as a promising drug target due to their role in various diseases like psychiatric disorders, stress-related diseases, chronic pain and in microbial infections. Bicyclic [4.3.1.] aza-amides have proven to be a privileged scaffold for FKBPs and serve as valuable starting point for the development of potent FKBP inhibitors. The aim of this thesis was to further improve the affinity, selectivity and metabolic stability of this compound class. The first part of the thesis was dedicated to the metabolic stability of these ligands. A series of deuterated derivatives was synthesized and a metabolite distribution analysis was conducted. This enabled the localization of metabolic soft spots and narrowed it down to two positions in the molecule. On the one hand, the N-alkyl-amide bond is readily cleaved by oxidative dealkylation. On the other hand, the carbon at the C4-position is prone to oxidation. In order to block the latter position, a novel tricyclic compound was synthesized, bridging the carbon C4 with the amide. The second part of the thesis was dedicated to the effect of a methyl group at the N-α-position. Various pairs of compounds with a methyl group in R- and in S-configuration were synthesized and tested for their binding affinities to FKBPs. All S-isomers displayed an increase in binding affinity, while the R-isomers displayed a significant decrease in binding affinity to all tested FKBPs. Molecular modelling studies were performed for a series of R-methyl, no methyl and S-methyl compounds. Energy maps were created for each compound allowing to determine preferred conformations and studying the effect of pre-organization of the ligand on binding affinity. A compound with an additional rotational barrier was synthesized in order to lock the conformation that most closely resembles the conformation found in the crystal structure. The third part of the thesis was dedicated to bicyclic [4.3.1] aza-amides with a 6-benzo[d]thiazol-2(3H)-one residue at the sulfone amide. This particular residue displayed sub-nanomolar binding affinity to FKBP12 and up to 1000-fold selectivity over FKBP51 and FKBP52. 45 derivatives were synthesized and tested for their binding affinities to FKBPs. Additionally, FP-assays were conducted with different FKBP12 constructs. In the fourth part, a small library of bicyclic [4.3.1] aza-amides with a modification of the vinyl group by Heck-reaction was synthesized. Elucidation of the crystal structures illustrated a vast space for substituents at this position enabling further contacts to the binding pocket. One derivative with a benzonitrile displayed 100-fold improved binding affinity for FKBP12, thus serving as a starting point for crystal structures and future optimizations. The fifth part was dedicated to modifications of different parts of the bicyclic [4.3.1] aza-amide scaffold in order to identify new positions for improvement. A novel series of sulfondiamides and sulfonamides as well as double-C5-substituted bicycles were synthesized and tested for their binding affinities.