Human Adipose Tissue 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibition Without Tachyphylaxis by Clofutriben, a Pseudo‐Irreversible Enzyme Inhibitor

Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), the pre-receptor regulator of intracellular active glucocorticoid levels, have promise to treat glucocorticoid excess whether endogenous (neoplastic or physiological elevated cortisol) or iatrogenic (glucocorticoid medicine toxicity). Three structurally distinct HSD-1 inhibitors have shown tachyphylaxis of pharmacodynamic activity in adipose, a key target tissue, suggesting that the clinical utility of the class might be limited by that pharmacological phenomenon. To determine whether the potent inhibitor clofutriben also showed adipose tachyphylaxis, HSD-1 activity was measured during daily oral clofutriben administration and infusion of mass-labeled enzyme substrate (cortisone) via microdialysis catheters placed in subcutaneous abdominal adipose of 12 persons with type 2 diabetes and obesity. During initial dosing, clofutriben was associated with dose-dependent decreases of mass-labeled HSD-1 product (cortisol) in adipose dialysate, from < 25% at 1 mg to > 90% at 6-10 mg. At steady state, all clofutriben doses were associated with > 90% decreases of mass-labeled cortisol in adipose dialysate with no evidence of tachyphylaxis. By surface plasmon resonance, clofutriben showed fast-on, slow-off (residence time 535 s) binding to human HSD-1. Molecular docking revealed that clofutriben can form a ternary complex with nicotinamide-adenine dinucleotide phosphate (NADPH) cofactor and the human HSD-1 active site. The higher activation energy to dissociate that trimolecular interaction, compared to a bimolecular drug-enzyme interaction characteristic of other HSD-1 inhibitors, is posited to be responsible for the enzyme kinetic and favorable pharmacological properties of clofutriben.