Ivan S. Koklin, Petr R. Lebedev, Alim A. Kochkarov, Oleg S. Gudyrev, Vladimir V. Gureev, Aleksandr A. Dolzhikov, Eduard I. Taran, Mikhail V. Korokin

Regulation of 11β-hydroxysteroid dehydrogenase isoforms – novel drug targets for osteoporosis therapy

Introduction

Regulation of 11β-hydroxysteroid dehydrogenase isoforms – novel drug targets for osteoporosis therapy. Explore 11β-hydroxysteroid dehydrogenase isoforms as novel drug targets for osteoporosis therapy. Discover how azole-based inhibitors can restore bone remodeling and repair.

Abstract

Introduction: Osteoporosis is an significant medical and social public health problem in an aging or elderly society, the issue of pharmacological correction of which remains unresolved to this day. Materials and Methods: The rationale for this idea stems from our previous findings on the role of 11B-HSD type 2 in bone remodeling and osteoreparation, combined with a content analysis and literature review of scientific publications from PubMed, Scopus, Cyberleninka, Google Scholar, and ResearchGate. Results and Discussion: Current understanding of the molecular mechanisms of bone homeostasis allows for a significant shift and expansion in the paradigms for treating and preventing osteoporosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key metabolic enzyme that catalyzes the intracellular conversion of inactive glucocorticoids into physiologically active ones. Research conducted over the past decade has shown that abnormal 11β-HSD1 activity contributes to the pathogenesis of obesity, type 2 diabetes, metabolic syndrome, and osteoporosis. The scientific challenge of regulating the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoforms and restoring homeostasis in the 11β-HSD1/11β-HSD2 enzymatic system is proposed to be addressed through the design and application of novel azole-based heterocyclic compounds as 11β-HSD1 inhibitors. Conclusion: The development of azole-based heterocyclic 11β-HSD1 inhibitors is expected to yield promising drug candidates for pharmacologically correcting impaired bone remodeling and repair.

Review

This review article proposes a compelling novel pharmacological strategy for the treatment of osteoporosis, a significant and growing public health concern with considerable unmet therapeutic needs. The core premise revolves around the critical role of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity in the pathogenesis of the disease. The authors effectively position 11β-HSD1, an enzyme responsible for converting inactive glucocorticoids into their active forms, as a key metabolic nexus linking osteoporosis with other prevalent metabolic disorders, thus identifying it as a promising and hitherto underexplored drug target for bone health. The rationale for this proposition is grounded in the authors' previous research on 11β-HSD type 2 in bone remodeling, supplemented by a comprehensive literature review spanning multiple scientific databases. The discussion elaborates on the expanding understanding of molecular mechanisms underlying bone homeostasis and how abnormal 11β-HSD1 activity contributes to bone pathology. Crucially, the paper moves beyond theoretical discussion by proposing a specific therapeutic direction: the design and application of novel azole-based heterocyclic compounds to selectively inhibit 11β-HSD1. This targeted intervention aims to restore the enzymatic balance within the 11β-HSD1/11β-HSD2 system, thereby mitigating the detrimental effects of excessive glucocorticoid action on bone. In conclusion, this article offers a significant and forward-thinking perspective on developing new therapeutic modalities for osteoporosis. By spotlighting 11β-HSD1 as a specific and mechanistically sound drug target, the authors lay a robust conceptual foundation for future research. The explicit suggestion of azole-based heterocyclic compounds as potential inhibitors provides a clear and actionable path for medicinal chemists and pharmacologists. If successfully translated into clinical applications, this research has the potential to yield truly innovative drug candidates that could fundamentally improve the pharmacological correction of impaired bone remodeling and repair, offering a much-needed advancement in osteoporosis therapy.

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