Therapeutics
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9 Semple, G et al. Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. Bioorg Med Chem Lett, 2011. 21(10): p. 3134-41. 10 Overton, HA et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small- molecule hypophagic agents. Cell Metab, 2006. 3(3): p. 167- 75. 11 Katsuma, S, Hirasawa, A and Tsujimoto, G. Bile acids promote glucagon-like peptide- 1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun, 2005. 329(1): p. 386-90. 12Watanabe, M et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 2006. 439(7075): p. 484-9. 13 Keitel, V et al. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun, 2008. 372(1): p. 78- 84. 14 Keitel, V et al. The G- protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology, 2007. 45(3): p. 695-704. 15 Thomas, C et al. TGR5- mediated bile acid sensing controls glucose homeostasis. Cell Metab, 2009. 10(3): p. 167- 77. 16 Milne, JC et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature, 2007. 450(7170): p. 712-6. 17 Zhang, QJ et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc Res, 2008. 80(2): p. 191-9.
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cortisone. Since cortisol increases insulin resistance, gluconeogenesis and glycogenolysis, the development of inhibitors for 11-HSD1 provides a potential therapeutic anti-diabetic approach. Indeed, the treat- ment of murine T2DM models with such an inhibitor improved insulin sensitivity, hyperglycemia and other glycemic parameters5. Moreover, this same study showed that 11-HSD1 inhibition was associ- ated with decreased weight gain in a mouse obesity model, as well as a decrease in lipid parameters and lesion size in a murine atherosclerosis model. The oral, selective 11-HSD1 inhibitor INCB13739, was tested in a Phase II clinical trial as a 12-week add-on therapy to metformin, and resulted in significant reductions in glycemic parameters, plasma lipid lev- els, and body weight6. However, a recently-published study with another 11-HSD1 inhibitor, MK-0916, reported only modest beneficial effects of a 12-week treatment in patients with T2DM and metabolic syn- drome7. Thus, further clinical studies are required to clarify the therapeutic interest of 11-HSD1 inhibitors to address multiple aspects of the metabol- ic syndrome and, in particular, T2DM.
GPR119: This G protein-coupled receptor (GPCR) is predominantly expressed in pancreatic -cells and in the gastrointestinal tract. GPR119 activation increases cAMP signalling, resulting in enhanced glucose-dependent insulin secretion and increased levels of GLP-1 and the related incretin GIP (Glucose-dependent Insulinotropic Peptide). Oral administration of small molecule GPR119 agonists has been shown to improve glucose tolerance in
rodents8, while molecules such as APD5979 and MBX-2982 are in clinical development. Similar to GLP-1 mimetics, GPR119 agonists are also expect- ed to have beneficial effects on obesity, and were indeed shown to decrease feeding, body weight gain, and adiposity in rats10. Thus, GPR119 repre- sents an attractive potential target for both T2DM and associated obesity, although its cardiovascular effects remain to be determined.
TGR5: This widely expressed bile acid-activated GPCR has recently emerged as an attractive ther- apeutic target in T2DM, obesity, NASH and the metabolic syndrome in general. Similar to GPR119, TGR5 activation in the intestine results in cAMP accumulation and enhanced GLP-1 secretion11. In addition, TGR5 activation in the skeletal muscle enhances energy expenditure via increased thyroid hormone activity, and may have beneficial effects on obesity and insulin resistance12. Finally, TGR5 activation in liver macrophages has anti-inflammatory effects13 and also enhances hepatic nitric oxide produc- tion14, with potential beneficial effects on bile acid homeostasis and diabetes-associated liver injury. Evidence of the therapeutic potential of TGR5 in T2DM and associated pathologies was provided by a report of the beneficial effects of the specific TGR5 agonist INT-777 on body weight, hepatic steatosis, preservation of liver and pancreatic function, and maintenance of glu- cose homeostasis and insulin sensitivity in mouse models15.
Table 1: Emerging therapeutic approaches to the global management of Type 2 diabetes Drug target 11β-HSD1 GPR119 TGR5 SIRT1 SGLT2 GPR40
Examples in development
INCB13739 MK-0916
APD597 MBX-2982
INT-777 SRT2104
Dapagliflozin BI-10773 LX4211
Unknown
Development phase
Phase II Phase II
Phase I Phase II
Regulatory pre-clinical
Phase II
Phase III Phase III Phase II
Pre-clinical ?
Mechanism of action
Inhibition of generation of cortisol from cortisone
insulin secretion incretins
GLP-1 secretion thyroid hormone activity
Activation of the NAD+- dependent deacetylase SIRT1 that regulates metabolism and life-span
renal glucose reabsorption
FFA-induced incretin secretion
PPARα/δ GFT505 Phase II
Specific PPAR agonism to address multiple
cardiometabolic risk factors Anti-diabetic therapeutic benefits
insulin resistance glycemia
Improved glucose tolerance
Improved glucose homeostasis and pancreatic function
insulin resistance glycemia
glucosuria Improved glucose homeostasis
Improved glucose tolerance (agonist) Improved insulin tolerance (antagonist)
insulin sensitivity Improved glucose homeostasis
Potential CV benefits
weight gain lipids
atherosclerosis weight gain
weight gain Liver function preservation
atherosclerosis I/R injury neointima
blood pressure Stroke protection
Unknown
dyslipidemia inflammation
liver dysfunction Drug Discovery World Summer 2011
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