Type 2 diabetes (T2D) is a chronic health condition that has reached alarming rates across the globe. The International Diabetes Federation (IDF) published the Diabetes Atlas, which estimated that 463 million adults had T2D worldwide in 2019. In addition, Recent studies have implicated aberrant glucocorticoid signaling as a cause of the development of several phenotypes that are associated with metabolic syndrome. Besides, an attractive therapeutic target is 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 is a key enzyme that acts as an NADPH-dependent reductase and converts inactive glucocorticoids (cortisone in humans and 11 dehydrocorticosterone in rodents) into the receptor-active glucocorticoids (cortisol in humans and corticosterone in rodents). In addition, this enzyme is highly expressed in metabolically active tissues, including the liver and adipose tissue, and regulates tissuespecific glucocorticoid levels. Hence, we will introduce a 11β-HSD1 inhibitor-SKI2852.

SKI2852 is a potent, selective, and orally active 11β-HSD1 inhibitor.

SKI2852 can inhibit mHSD1 and hHSD1, with IC₅₀s of 1.6 nM and 2.9 nM, respectively. Furthermore, the amide carbonyl group of SKI2852 established a central hydrogen bond interaction with the hydroxyl side chain of Ser170, one of the key residues (Ser170, Tyr183, and Lys 187) that define the catalytic triad for 11β-HSD1 activity.

In vitro, SKI2852 inhibits 11β-HSD1 with an IC₅₀ of 4.4 ± 0.5 nM in HEK293 cells stably transfected with human 11β-HSD1 cDNA.

In vivo, SKI2852 (20 mg/kg; oral; once daily for 25 days) significantly reduces blood glucose and HbA1c levels. Moreover, SKI2852 improved the lipid profiles in ob/ob mice and suppressed hepatic mRNA levels of gluconeogenic enzymes. Furthermore, SKI2852 clearly enhanced hepatic and whole-body insulin sensitivities in a hyperinsulinemic-euglycemic clamp experiment in DIO mice.

In a word, SKI2852 is a promising 11β-HSD1 inhibitor for metabolic disease research.

Reference:

[1] Ryu JH, et al. J Med Chem. 2016 Nov 23;59(22):10176-10189.

[2] Tinajero MG, et al. Endocrinol Metab Clin North Am. 2021 Sep;50(3):337-355.