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A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits.

Anil TM, Dandu A, Harsha K, Singh J, Shree N, Kumar VS, Lakshmi MN, Sunil V, Harish C, Balamurali GV, Naveen Kumar BS, Gopala AS, Pratibha S, Sadasivuni M, Anup MO, Moolemath Y, Venkataranganna MV, Jagannath MR, Somesh BP - BMC Pharmacol Toxicol (2014)

Bottom Line: The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance.A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Connexios Life Sciences Pvt Ltd, Bangalore, India. m.r.jagannath@connexios.com.

ABSTRACT

Background: 11ß-hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and 'pan tissue' acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome.

Methods: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively.

Results: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC50 = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.

Conclusions: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

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Related in: MedlinePlus

Potency and selectivity of CNX-010-49. Inhibition curve with increasing concentrations of CNX-010-49 for reductase activity in CHOK1 cells stably expressing human 11β-HSD1 (A), Mouse C2C12 cells (B), fully differentiated human adipocytes (C), both reductase and dehydrogenase activity with recombinant human 11β-HSD1 protein (D) as mentioned in the materials and methods. Selectivity of CNX-010-49 (100 μM) against HSD related enzymes were evaluated in CHOK1 cells transiently over expressing human 11βHSD2 and 17β HSD3 respectively (E & G) and T47D cells for 17βHSD1 (F). Data are means of three individual experiments with standard deviations (n = 6).
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Figure 1: Potency and selectivity of CNX-010-49. Inhibition curve with increasing concentrations of CNX-010-49 for reductase activity in CHOK1 cells stably expressing human 11β-HSD1 (A), Mouse C2C12 cells (B), fully differentiated human adipocytes (C), both reductase and dehydrogenase activity with recombinant human 11β-HSD1 protein (D) as mentioned in the materials and methods. Selectivity of CNX-010-49 (100 μM) against HSD related enzymes were evaluated in CHOK1 cells transiently over expressing human 11βHSD2 and 17β HSD3 respectively (E & G) and T47D cells for 17βHSD1 (F). Data are means of three individual experiments with standard deviations (n = 6).

Mentions: CNX-010-49 is a highly potent 11β-HSD1 inhibitor towards both human and mouse isoforms with an IC50 of 6 nM and 64 nM respectively (Figure 1A & B) as established from cells over expressing human 11β-HSD1 in CHO-K1 cell and fully differentiated mouse C2C12 myotubes respectively. IC50 for CNX-010-49 in primary human mature adipocytes is 13 nM (Figure 1C). CNX-010-49 inhibits reductase activity more than dehydrogenase activity (>100X, Figure 1D). CNX-010-49 is highly selective inhibitor with no inhibition up to 100 μM towards 11β-HSD2, 17β-HSD1 and 17β-HSD3 (Figure 1E, F & G). In a single dose pharmacodynamic activity evaluation in Swiss albino mice, oral administration of CNX-010-49 at 30 mg/kg inhibited 11β-HSD1 activity by 58% and 24% at 1 h and 7 h respectively in liver. In adipose, the inhibition was 41% at 1 h and continued to be same till 7 h. In skeletal muscle, the inhibition was ~38% at 1 h and 7 h. At end of 24 h, there was no inhibition of 11β-HSD1 observed (data not shown). However there was no inhibition observed in brain (Table 1).


A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits.

Anil TM, Dandu A, Harsha K, Singh J, Shree N, Kumar VS, Lakshmi MN, Sunil V, Harish C, Balamurali GV, Naveen Kumar BS, Gopala AS, Pratibha S, Sadasivuni M, Anup MO, Moolemath Y, Venkataranganna MV, Jagannath MR, Somesh BP - BMC Pharmacol Toxicol (2014)

Potency and selectivity of CNX-010-49. Inhibition curve with increasing concentrations of CNX-010-49 for reductase activity in CHOK1 cells stably expressing human 11β-HSD1 (A), Mouse C2C12 cells (B), fully differentiated human adipocytes (C), both reductase and dehydrogenase activity with recombinant human 11β-HSD1 protein (D) as mentioned in the materials and methods. Selectivity of CNX-010-49 (100 μM) against HSD related enzymes were evaluated in CHOK1 cells transiently over expressing human 11βHSD2 and 17β HSD3 respectively (E & G) and T47D cells for 17βHSD1 (F). Data are means of three individual experiments with standard deviations (n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4127523&req=5

Figure 1: Potency and selectivity of CNX-010-49. Inhibition curve with increasing concentrations of CNX-010-49 for reductase activity in CHOK1 cells stably expressing human 11β-HSD1 (A), Mouse C2C12 cells (B), fully differentiated human adipocytes (C), both reductase and dehydrogenase activity with recombinant human 11β-HSD1 protein (D) as mentioned in the materials and methods. Selectivity of CNX-010-49 (100 μM) against HSD related enzymes were evaluated in CHOK1 cells transiently over expressing human 11βHSD2 and 17β HSD3 respectively (E & G) and T47D cells for 17βHSD1 (F). Data are means of three individual experiments with standard deviations (n = 6).
Mentions: CNX-010-49 is a highly potent 11β-HSD1 inhibitor towards both human and mouse isoforms with an IC50 of 6 nM and 64 nM respectively (Figure 1A & B) as established from cells over expressing human 11β-HSD1 in CHO-K1 cell and fully differentiated mouse C2C12 myotubes respectively. IC50 for CNX-010-49 in primary human mature adipocytes is 13 nM (Figure 1C). CNX-010-49 inhibits reductase activity more than dehydrogenase activity (>100X, Figure 1D). CNX-010-49 is highly selective inhibitor with no inhibition up to 100 μM towards 11β-HSD2, 17β-HSD1 and 17β-HSD3 (Figure 1E, F & G). In a single dose pharmacodynamic activity evaluation in Swiss albino mice, oral administration of CNX-010-49 at 30 mg/kg inhibited 11β-HSD1 activity by 58% and 24% at 1 h and 7 h respectively in liver. In adipose, the inhibition was 41% at 1 h and continued to be same till 7 h. In skeletal muscle, the inhibition was ~38% at 1 h and 7 h. At end of 24 h, there was no inhibition of 11β-HSD1 observed (data not shown). However there was no inhibition observed in brain (Table 1).

Bottom Line: The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance.A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Connexios Life Sciences Pvt Ltd, Bangalore, India. m.r.jagannath@connexios.com.

ABSTRACT

Background: 11ß-hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and 'pan tissue' acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome.

Methods: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively.

Results: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC50 = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.

Conclusions: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

Show MeSH
Related in: MedlinePlus