Novel nonsteroidal inhibitors of the human 11-beta hydroxysteroid dehydrogenase type 1 enzyme for the treatment of obesity and metabolic syndrome

Nontumoral cortisol dysregulation in obese individuals is associated with many facets of metabolic syndrome, including central adiposity, diabetes mellitus (T2DM), dyslipidemia, and hypertension. Glucocorticoid availability and function at the cell/tissue level are classically regulated by 11-beta hydroxysteroid dehydrogenase type (11β-HSD) enzymes. The 11β-HSD1 enzyme is expressed primarily in the liver and adipose tissue (AT) where cortisone in converted into its active form, cortisol. 11β-HSD1 expression in AT promotes adipocyte proliferation and hypertension, leading to the development of abdominal obesity and comorbidities. The 11β-HSD1 enzyme is a key therapeutic target for modulating obesity and associated metabolic disorders.In response to this need, our research aimed to design and characterize a family of nonsteroidal compounds displaying specific and selective inhibition of the 11β-HSD1 enzyme. For this purpose, we designed, synthetized, and characterized a family of adamantyloxadiazole compounds to selectively inhibit the human 11β-HSD1 enzyme that are henceforth designated sequentially from A to N (14 compounds). Our newly synthesized compounds were designed in silico and synthesized via retrosynthesis. We tested the following properties of our novel compounds: (1) their biopharmaceutical properties, (2) their inhibitory potency (IC50) over 11β-HSD1 reductase activity in cell-free assays, and (3) their relative inhibitory potency and IC50 in human adipocytes.Biopharmaceutical characterization of the compounds revealed high transcellular permeability and no interaction with P-glycoprotein, a known efflux pump that decreases oral systemic and central exposure, for Compounds J and L . In vitro studies of the inhibition of the 11β-HSD1 enzyme via cell-free and microsome-based assays indicated significant inhibitory potency, with optimal specificity and selectivity observed at the nanomolar level, highlighting both the IC50 values of Compound J (11,8 nM) and Compound L (3,9 nM), which also preserve 11b-HSD oxidase activities (> 90%). In human adipocytes, 1 µM Compounds E , J and L demonstrated a high potency of 11β-HSD1 inhibition, near 40–60%, compared to 1 µM inhibitor carbenoxolone, which showed approximately a 90% inhibition.The preclinical evaluation of these adamantyloxadiazole derivatives revealed their potential as effective inhibitors of the 11β-HSD1 enzyme, with Compounds E , J and L showing particularly relevant performance in vitro . These findings support the progression of in vivo studies to further explore their therapeutic potential in treating obesity and associated metabolic disorders.