Elsevier

European Journal of Pharmacology

Volume 768, 5 December 2015, Pages 139-148
European Journal of Pharmacology

Endocrine pharmacology
A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models

https://doi.org/10.1016/j.ejphar.2015.10.042Get rights and content

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) has been targeted for new drugs to treat type 2 diabetes and metabolic syndrome. In this study, we determined whether the inhibition of 11βHSD1 with a new selective inhibitor, SKI2852, could improve lipid profiles, glucose levels, and insulin sensitivity in type 2 diabetic and obese conditions. SKI2852 showed a potent inhibition of cortisone to cortisol conversion for over 80% in both liver and adipose tissue ex vivo from orally administered C57BL/6 mice, and in vivo analysis results were consistent with this. Repeated oral administrations of SKI2852 in diet-induced obesity (DIO) and ob/ob mice revealed a partially beneficial effect of SKI2852 in improving levels of cholesterols, triglycerides, free fatty acids, postprandial glucose, and/or blood hemoglobinA1c. SKI2852 significantly reduced body weight increase in ob/ob mice, and efficiently suppressed hepatic mRNA levels of gluconeogenic enzymes in DIO mice. Moreover, SKI2852 enhanced hepatic and whole body insulin sensitivities in hyperinsulinemic-euglycemic clamp experiment in DIO mice. In conclusion, these results indicate that selective and potent inhibition of 11βHSD1 by SKI2852, thus blockade of active glucocorticoid conversion, may improve many aspects of metabolic parameters in type 2 diabetes and metabolic diseases, mainly by inhibitions of hepatic gluconeogenesis and partial improvements of lipid profiles. Our study strongly support that SKI2852 may have a great potential as a novel candidate drug for the treatment of diabetes and metabolic diseases.

Introduction

Type 2 diabetes mellitus is a disease with combined pathologies of metabolic abnormalities, such as dyslipidemia, hyperglycemia, and insulin resistance (Day, 2007), and despite of current pharmaceutical advances, there are still immediate un-met needs for improved therapies. Previous studies have implicated prolonged exposure to glucocorticoids as causes of the development of metabolic syndrome (Walker and Seckl, 2003). Active glucocorticoids up-regulate gluconeogenesis in the liver via glucocorticoid receptor-mediated regulation of downstream target gene expressions or activities (Drake et al., 2005).

In this respect, an attractive biological target is 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) (Joharapurkar et al., 2012). Although active glucocorticoids are produced from adrenal cortex (Jeong et al., 2004b), they can also be generated locally by the actions of 11βHSD1 in other tissues (Pereira et al., 2012). The 11βHSD1 converts inactive glucocorticoids (cortisone in human and 11-dehydrocorticosterone in rodent) into active glucocorticoids (cortisol in human and corticosterone in rodent), and is highly expressed in metabolically active tissues including liver (Baudrand et al., 2010). The hepatic 11βHSD1 gene expression is also correlated positively with fasting insulin levels and insulin resistance in obese human (Baudrand et al., 2011).

The connection between type 2 diabetes and 11βHSD1 has been suggested in mouse genetic models. Transgenic mice overexpressing 11βHSD1 in adipose tissue showed features of metabolic syndrome including obesity, dyslipidemia, glucose intolerance, and hypertension (Masuzaki et al., 2001, Masuzaki et al., 2003). Conversely, 11βHSD1-deficient mice demonstrated reduction in body weight and triglyceride levels, and induction in insulin sensitivity, when maintained on a high-fat diet (HFD) (Morton et al., 2004). In addition, liver-specific overexpression of 11βHSD1 in transgenic mice caused insulin resistance without obesity (Paterson et al., 2004), while liver-specific deletion of 11βHSD1 prevented 11-dehydrocorticosterone-induced obesity and insulin resistance (Harno et al., 2013a). Moreover, 11βHSD1 deficiency in apoE-deficient mice reduced and delayed atherosclerosis symptoms (García et al., 2013). Altogether, these combined findings suggest that 11βHSD1 could be a promising target for the treatment of metabolic syndrome as well as type 2 diabetes.

Recently, a number of small molecule 11βHSD1 inhibitors have been reported (Anagnostis et al., 2013). Among them, AMG-221 (BVT-83370, Amgen-Biovitrum) has been proven its efficacy in a phase I study (Gibbs et al., 2011). Similarly, BVT.2733 (Biovitrum) has been shown to enhance hepatic insulin sensitivity in diabetic mice models (Alberts et al., 2003). More recently, a clinical candidate BI-135585 (Boehringer Ingelheim & Vitae) has been demonstrated to potently inhibit 11βHSD1 in primate models (Hamilton et al., 2015). Several other 11βHSD1 inhibitors, such as PF-915275 (Pfizer) (Bhat et al., 2008), are among promising candidates for metabolic syndrome and type 2 diabetes, some of them currently being tested in clinical trials.

We have developed 11βHSD1 inhibitors over the past several years. In particular, SKI2852 is a promising novel candidate for anti-metabolic syndrome and anti-diabetes drug. In the present study, we evaluated SKI2852 for 11βHSD1 inhibition potency, for metabolic efficacy in several metabolic disease mice models, and for enhancement of hepatic and whole body insulin sensitivities.

Section snippets

Materials

SKI2852(2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide) and AMG-221 (Supplemental Fig. 1A) were synthesized by us at SK Chemicals. All other materials were purchased from Sigma-Aldrich (St. Louis, MO).

Animal husbandry

Eight-week old male C57BL/6 and C57BL/6-Lepob (ob/ob) mice (Charles River Laboratories Japan, Yokohama, Japan) were used in this study. In addition, eight-week old male KK-Ay/J (KK-Ay; Jackson Laboratory,

Characterization of SKI2852 as an 11βHSD1 inhibitor

To determine pharmacological characterization, we first analyzed inhibitory potency of SKI2852 for 11βHSD1 enzyme activity in vitro and compared with AMG-221 (Supplemental Fig. 1B). SKI2852 showed an inhibition in low nanomolar concentrations for human (h11βHSD1) and mouse 11βHSD1 (m11βHSD1) enzyme activities in HEK293 microsomal fractions or in HEK293 cells stably transfected with h11βHSD1 (HEK293-h11βHSD1), judged by calculated IC50 values (2.9 nM for h11βHSD1, 1.6 nM for m11βHSD1, and 4.4 nM

Discussion

In this study, we evaluated SKI2852 for 11βHSD1 inhibition activity, for metabolic efficacy in several disease mice models, and for enhancement of whole body and hepatic insulin sensitivities. We showed that SKI2852 is a selective 11βHSD1 inhibitor which potently inhibits cortisone to cortisol conversion. SKI2852 has significantly lowered body weight gains in ob/ob mice and partially improved lipid profiles in DIO, ob/ob, and KK-Ay mice models. It also has efficiently reduced postprandial

Declaration of interests

H.Y.H., H.J.S., H.J.L., S.K., J.H.S., and J.H.R. are employees of SK Chemicals. The authors declare that they have no vested interest that could be construed to have inappropriately influenced this study.

Contributor statements

H.Y.H., S.K., and J.H.R. planned the project, H.O., J.H.R., and C.S.C. designed the experimental studies, S.K. and J.H.R. performed medicinal chemistry, H.J.S. and H.J.L. performed biochemical and cell-based analyses, H.J.S., J.H.S., and H.Y.H. performed ex vivo and in vivo inhibition analyses, H.O., H.Y.H., H.J.S., and S.S.K. performed mouse model experiments, H.O., K.-H.J., J.H.R., and C.S.C. analyzed data, K.-H.J. wrote the manuscript, and K.-H.J., H.-S.J., J.H.R., and C.S.C. reviewed and

Acknowledgments

We thank Dr. Gildon Choi for generating and providing HEK293 cells stably transfected with 11βHSD1 cDNAs. This study was supported in part by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Korea (HI14C1135 and HI15C0987 to C.S.C.).

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    These authors contributed equally to this work.

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