Polycyclic group optimization in 11β-HSD1 inhibitors and their pharmacological evaluation

The present PhD Thesis evolves around the design, synthesis and pharmacological evaluation of novel 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. Given that the enzyme active site includes a hydrophobic pocket to accommodate bulky lipophilic scaffolds, the main objective was focused on the study of new 11β-HSD1 inhibitors exploring different hydrophobic polycyclic substituents. 11β-HSD1 catalyzes the cortisol regeneration from its inactive form cortisone in tissues mainly expressing glucocorticoid (GC) receptors, such as liver, adipose and brain. GCs are well known hormones that play a major role in our organism. It is well accepted that the GC concentration in peripheral tissues not only depends on the adrenal secretion but also on the intracellular metabolism in these tissues, namely by 11β-HSD1. During the last years, both academia and industry have made great efforts to develop 11β-HSD1 inhibitors to target diseases such as type 2 diabetes and Alzheimer’s. The general structure of these molecules consists on a bulky lipophilic group –usually an adamantyl- linked by an amide core to a right-hand side (RHS) substituent. The first goal was the development of a new polycyclic amine, the 2-oxaadamantan-5- amine, to add to our library of polycyclic substituents (Chapter 3). The target amine was envisioned to contain an oxygen atom in its hydrophobic skeleton to mimic the structure of some hydroxylated adamantyl derivatives in development. Its synthesis involved consecutive Criegee rearrangements on 2-methyl-2-adamantanol to deliver the 2- oxaadamantane, which was then functionalized by C-H activation using phase-transfer catalysis. Finally, a Ritter reaction followed by deprotection with thiourea delivered the desired 2-oxaadamantan-5-amine. The second objective of the present thesis was the synthesis of a small series of 1- and 2-adamantyl-based 11β-HSD1 inhibitors, as most of the 11β-HSD1 inhibitors evaluated are 2-adamantyl substituted derivatives and no comparison with their C-1 isomers was available. Moreover, considering that very few heteroadamantanes have been studied in 11β-HSD1 inhibitors, we also evaluated the introduction of the previously synthesized 5-substituted 2-oxaadamantane (Chapter 4). 1 Focusing on the main goal, it is reported the exploration of other hydrophobic polycyclic substituents as replacement of adamantane with a design supported by molecular modeling studies in order to optimize the filling of the hydrophobic pocket in the binding site (Chapter 5). This work let us to a new family of potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. The in vitro biological profiling of the compounds permitted us to select a proper candidate for an in vivo study in a rodent model of cognitive dysfunction. The results supported the neuroprotective effect of 11β- HSD1 inhibition in cognitive decline related to the aging process, since the treatment prevented memory deficits through a reduction of neuroinflammation and oxidative stress, and an increase of the abnormal proteins degradation in the brain. An additional in vivo study in a model of cognitive dysfunction and metabolic disease is currently ongoing to study how 11β-HSD1 inhibition can modulate these two linked disorders, as so-called type 3 diabetes. Finally, the focus was on the exploration of different substituents in the RHS of the molecule to further improve potency, selectivity and metabolic stability. The endeavour started integrating different aromatic, heteroaromatic, heterocycloalkyl and branched alkyl substituents generating diversity to build some structure-activity relationship (SAR) information (Chapter 6). From this work we obtained potent nanomolar inhibitors but still without the needed selectivity and stability properties. In light of these results, we started a rational design of new substitution patterns in order to establish additional interactions that would deliver more potent and selective inhibitors (Chapter 7). The pharmacological tests revealed some low nanomolar activities together with good metabolic stabilities, although selectivity over the isoenzyme 11β-HSD2 remains a challenge to be accomplished