title: 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.
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.
authors.forename: Tharappel M
authors.initials: TM
authors.lastname: Anil
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Dandu
authors.forename: KrishnaReddy
authors.initials: K
authors.lastname: Harsha
authors.forename: Jaideep
authors.initials: J
authors.lastname: Singh
authors.forename: Nitya
authors.initials: N
authors.lastname: Shree
authors.forename: Venkatesh Satish
authors.initials: VS
authors.lastname: Kumar
authors.forename: Mudigere N
authors.initials: MN
authors.lastname: Lakshmi
authors.forename: Venkategowda
authors.initials: V
authors.lastname: Sunil
authors.forename: Chandrashekaran
authors.initials: C
authors.lastname: Harish
authors.forename: Gundalmandikal V
authors.initials: GV
authors.lastname: Balamurali
authors.forename: Baisani S
authors.initials: BS
authors.lastname: Naveen Kumar
authors.forename: Aralakuppe S
authors.initials: AS
authors.lastname: Gopala
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Pratibha
authors.forename: ManojKumar
authors.initials: M
authors.lastname: Sadasivuni
authors.forename: Mammen O
authors.initials: MO
authors.lastname: Anup
authors.forename: Yoganand
authors.initials: Y
authors.lastname: Moolemath
authors.forename: Marikunte V
authors.initials: MV
authors.lastname: Venkataranganna
authors.affiliation: Connexios Life Sciences Pvt Ltd, Bangalore, India. m.r.jagannath@connexios.com.
authors.forename: Madanahalli R
authors.initials: MR
authors.lastname: Jagannath
authors.forename: Baggavalli P
authors.initials: BP
authors.lastname: Somesh
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006943:Hyperglycemia / Q000188:drug therapy*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002316:Cardiotonic Agents; D042842:11-beta-Hydroxysteroid Dehydrogenases
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