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

Guohua An; Julio A Gutierrez; Cele Abad-Zapatero; Shin-Kai Lin; Caleb Schmicker; Aimee Rinas; Brian Engel; Tobias Magers; Tonya K Marmon; David A Katz

doi:10.1111/cts.70398

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

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

Guohua An, Julio A Gutierrez, Cele Abad-Zapatero, Shin-Kai Lin, Caleb Schmicker, Aimee Rinas, Brian Engel, Tobias Magers, Tonya K Marmon and David A Katz

Clinical and translational science, Vol.18(11), e70398

11/2025

DOI: 10.1111/cts.70398

PMCID: PMC12619576

PMID: 41240060

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Abstract

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.

11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors

11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemistry

11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism

Adipose Tissue - drug effects

Adipose Tissue - enzymology

Adult

Cortisone - metabolism

Diabetes Mellitus, Type 2 - drug therapy

Diabetes Mellitus, Type 2 - enzymology

Dose-Response Relationship, Drug

Enzyme Inhibitors - administration & dosage

Enzyme Inhibitors - pharmacokinetics

Enzyme Inhibitors - pharmacology

Female

Humans

Hydrocortisone - metabolism

Male

Middle Aged

Molecular Docking Simulation

Obesity - drug therapy

Obesity - enzymology

Pyridines - administration & dosage

Pyridines - pharmacokinetics

Pyridines - pharmacology

Details

Title: Subtitle: Human Adipose Tissue 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Without Tachyphylaxis by Clofutriben, a Pseudo-Irreversible Enzyme Inhibitor
Creators: Guohua An - University of Iowa
Julio A Gutierrez - Scripps Clinic
Cele Abad-Zapatero - University of Illinois Chicago
Shin-Kai Lin - Eurofins Discovery, Taipei, Taiwan
Caleb Schmicker - IQVIA (United Kingdom)
Aimee Rinas - IQVIA (United Kingdom)
Brian Engel - IQVIA (United Kingdom)
Tobias Magers - IQVIA (United Kingdom)
Tonya K Marmon - Cancer Research And Biostatistics
David A Katz - Sparrow Hospital
Resource Type: Journal article
Publication Details: Clinical and translational science, Vol.18(11), e70398
DOI: 10.1111/cts.70398
PMID: 41240060
PMCID: PMC12619576
NLM abbreviation: Clin Transl Sci
ISSN: 1752-8062
eISSN: 1752-8062
Publisher: WILEY
Grant note: Sparrow Pharmaceuticals, Portland OR USA
This work was supported by Sparrow Pharmaceuticals, Portland OR USA.
Language: English
Date published: 11/2025
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9985027466302771

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