Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes

Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (HSD1) inhibitor in humans: liver and adipose tissue 11β‐HSD1 inhibition after acute and multiple administrations over 2 weeks

“…Insufficient inhibition of 31 and 5%, respectively, could only be shown in the 100-and 200-mg groups, despite AT compound concentrations in the expected range. The expected enzyme inhibition and BI 135585 concentration in AT was based on preclinical modelling [16]. From those preclinical data, >90% 11 -HSD1 inhibition in AT after single and repeated dosing was defined to be the prerequisite for clinical development of BI 135585.…”

“…Plasma samples for pharmacokinetic analysis were obtained on days 1 and 14 (pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 h), days 2-13 (pre-dose), [15][16][17][18][19]21 and 24 (in the morning). The 24-h urinary collection for pharmacokinetic/pharmacodynamic analysis was obtained from days 1-2, and days 11-15 at 4-12-h intervals.…”

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

“…The enzyme 11β‐HSD1 is considered to be critical in the development of metabolic syndrome and thus a therapeutic target for treating type‐2 diabetes . The clinical candidates ( S )‐6‐(2‐hydroxy‐2‐methylpropyl)‐3‐(( S )‐1‐(4‐(1‐methyl‐2‐oxo‐1,2‐dihydropyridin‐4‐yl)phenyl)ethyl)‐6‐phenyl‐1,3‐oxazinan‐2‐one (1) and (4a R ,9a S )‐1‐(1 H ‐benzo[d]midazole‐5‐carbonyl)‐2,3,4,4a,9,9a‐hexahydro‐1‐ H ‐indeno[2,1‐b]pyridine‐6‐carbonitrile hydrochloride (2), Figure , inhibit the conversion of cortisone to cortisol with nanomolar potency, an average IC 50 of 11nM in human adipose tissue ex vivo in case of (1) . Herein, we describe the synthesis of these 2 compounds labeled with carbon‐13 and carbon‐14.…”

Invitro and Invivo Inhibition of Metyraponemetabolism by Glycyrrhetinic Acid in Male Wistar Rats

“…Considering that the extensive difference was not observed in the sum of AUC 6h of MP and MPOL between MP alone and GA combination, even though the pharmacokinetics of MP and its metabolites were modified by 11β-HSD1 inhibitor, suggesting a low potential to affect the pharmacological activity of MP. Recently, drugs which inhibit 11β-HSD1 have been developed to treat obesity [22][23][24]. From the present evidence, it would be expected that the administration of MP with an 11β-HSD1-inhibiting drug to humans may modulate the pharmacokinetics of MP and its metabolites.…”