NASH Target Development Service for 11 β-HSD1 Inhibitors

In the liver and adipose tissue, 11 β-hydroxysteroid dehydrogenase type1 (11 β-HSD1) inhibitors play a key role in the conversion of inactive cortisone to active cortisol that can be thought of as a potential target for nonalcoholic steatohepatitis (NASH) therapy. As a long-term expert in drug discovery, Creative Biolabs is professional in disease target development (such as target screening, structural characterization, and functional analysis) for identifying potential drug targets. Currently, our experienced scientists are dedicated to offering a wide range of 11β-HSD1 inhibitors as NASH therapeutics.

Introduction of 11β-HSD1 Inhibitors

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is also known as cortisone reductase, which converts inactive glucocorticoid (GC) into active GC, such as cortisol in humans, in metabolically relevant tissues like liver, adipose tissue, and skeletal muscles. Chronically elevated cortisol activity is associated with metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, and cardiovascular complications. At present, inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. It has been well tolerated and has improved glycemic control, lipid profile and blood pressure in clinical trials. The known inhibitors of 11β-HSD1 could be divided into several groups:

• Endogenous substances
• Exogenous natural products and their derivatives
• Synthetic small organic molecules from different classes of heterocyclic compounds

Selective inhibitors of 11β-HSD1 have been proposed as a strategy to suppress glucocorticoid action in several metabolic disorders, such as type 2 diabetes mellitus, obesity, insulin resistance, and non-alcoholic fatty liver disease.

Fig.1 11β-HSD1 and regeneration of cortisol. (Harno, 2010)

11β-HSD1 Inhibitors for the Treatment of NASH

NASH is regarded as the hepatic manifestation of the metabolic syndrome, characterized by steatosis, inflammation, and fibrosis. GCs have wide-ranging actions that modulate many of the pathological processes that occur during tissue injury and repair and contribute to liver fibrosis. Tissue GC levels are regulated by the intracellular enzyme 11β-HSD1, which is highly abundant in liver and can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Therefore, inhibition of 11β-HSD1 has been suggested as a potential treatment for NASH. In the global 11β-HSD1 deficiency mice, markers of hepatic inflammation are increased, suggesting a critical role for 11β-HSD1 in restraining the transition to NASH. In human clinical studies, NASH patients with pharmacological inhibition of 11β-HSD1 show modest reduction of liver fat content over a 12-week treatment period. In summary, 11β-HSD1 influences hepatic lipid accumulation and its inhibitors may be a potential therapy for NASH by restraining hepatic inflammation.

Fig.2 Schematic representation of the effects of cortisol in steatotic and non-steatotic liver transplantation from brain dead donors. (Jiménez-Castro, 2017)

11β-HSD1 Inhibitors Development at Creative Biolabs

Targeting the dominant pathogenic pathway and discovering effective and safe pharmacological treatment may be the future for NASH patients. With advanced technologies and professional team, Creative Biolabs is one of the well-recognized service providers in disease target development and drug discovery. We can offer one-stop and fully customized drug discovery service to satisfy clients’ demands. Remarkably, we have already launched the following small molecule development strategies for novel 11β-HSD1 inhibitors, including Hit identification, Hit to Lead, Target Identification and Validation, Lead Optimization.

Our one-stop drug discovery platforms can meet every special project requirement in the quality and timeline. At present, we can provide various 11β-HSD1 inhibitors and other useful targets as NASH treatment strategy. Our diversiform services run through the entire NASH drug development process, including Biomarkers for NASH Diagnosis, Target Discovery and Therapeutic Strategies and Preclinical Models of NASH.

If you have any other requests for NASH services, please feel free to contact us or directly send us a quote.

References

1. Harno, E.; White, A. Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis? Trends in Endocrinology & Metabolism. 2010, 21(10): 619-627.
2. Jiménez-Castro, M.B.; et al. The effect of cortisol in rat steatotic and non-steatotic liver transplantation from brain-dead donors. Clinical Science. 2017, 131(8): 733-746.