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What Is Gpr119 And How Compound Psn821 Might Work

Two weeks ago I wrote about the most promising new diabetes therapies and many of you wanted to know more so this week, Skott Lant, Doctor of Pharmacy Candidate UF College of Pharmacy has prepared a report on What Gpr119 is And How Compound Psn821 Might Work. This is a dual mechanisms of action, first in class, essentially providing two drug classes in one pill and is taken orally.

What Is Gpr119 And How Compound Psn821
Might Work.

C. Skott Lant Doctor of Pharmacy Candidate
UF College of Pharmacy

A novel target, GPR 119, for Diabetes Mellitus Type 2 is currently in Phase I development by both OSI Pharmaceuticals and Arena Pharmaceuticals augmenting the changeover to incretin-based, beta-cell preserving and BMI-stabilizing therapies which are the future of diabetes treatments. This G-protein coupled receptor, also known as glucose-dependent insulinotropic receptor (GDIR) is expressed in the highest density in both the ileum/colon and the pancreas. The promise and the excitement over these new therapies is that they are orally available agonists for GPR 119/ GDIR with dual mechanisms of action, essentially providing two drug classes in one pill.

In last week’s newsletter, it was mentioned that DPP-IV inhibitors and GLP-1 analogues are moving up the diabetes treatment ladder due to their lower risks of hypoglycemia and worries over CV risk with PPAR-γ agonists. Also, the tried and true therapies can significantly increase BMI, while incretin-based therapies have been shown to help with weight loss and preserve pancreatic β-cell function.

While GLP-analogues, exenatide and liraglutide are administered by SC injection, these new compounds are orally available and are more potent than with IV administration. One way they work is by mimicking the free-fatty acid amides which normally activate the GPR119/GDIR located on the L-cells on the lumen of the lower intestine. Activation of the receptor leads to a Gs-based increase in cAMP intracellular concentrations and secretion of GLP-1 at physiologic levels into the bloodstream where it exerts its anti-diabetic effects on pancreatic, gastric and CNS tissues. But this is only 50% of the effect produced by these novel compounds.

GPR119/GDIR is also densely expressed directly on pancreatic β-cells. In a 2007 study by Chu et al, it was shown that activation of these receptors increases glucose-dependent insulin release and increase oral glucose tolerance, but only in mice with the GPR119 receptor and not in mice lacking the GDIR target. Additionally, OSI claims that there is no loss of efficacy with repeated administration. So the other 50% of the GPR119/GDIR agonists biological activity is due to glucose-sensitive insulin release directly from the β-cells.

A June 2008 mini review in the Journal of Biological Chemistry and supported by the NIH, recognizes FFARs (Free Fatty Acid Receptors), including GPR119 as promising therapeutic targets for the treatment of Type II Diabetes Mellitus. This novel agent has the potential to be an orally available hybrid of a GLP-analogue and a sulfonylurea without the concomitant hypoglycemic risk and weight gain. In fact weight loss is more likely to be the result. With the addition of a DPP-IV inhibitor like Januvia, a robust new strategy for treatment is looming on the horizon. We’ll keep you posted as OSI and Arena bring these products closer to market

  • GDIR is endogenously activated by non-specific free fatty acid’s.
  • GDIR receptors are located in the colon:
    • upon activation, they release incretins (GLP-1) into the bloodstream.
  • The Antidiabetic effects of incretins include:
    • Increased insulin and decreased glucagon release
    • Increased β-cells proliferation and decreased β-cells apoptosis
    • Delayed gastric emptying and decreased acid release
    • Feelings of increased satiety and decreased appetite.
  • GDIR receptors are also located on pancreatic β-cells:
    •  which helps maintain glucose homeostasis by improving glucose-dependent insulin release, similar to the effects of meglitinides.
  • OSI & Arena Pharmeceuticals are developing highly specific agonists for these receptors first described in 2006.
References:
L. Lauffer, R. Iakoubov and P. L. Brubaker. GPR119: "Double-Dipping" for Better Glycemic Control. Endocrinology. 2008 May;149(5):2038-47.
Overton HA, Fyfe MC, Reynet C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol. 2008 Mar;153 Suppl 1:S76-81. Epub 2007 Nov 26.
Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology. 2008 May;149(5):2038-47. Epub 2008 Jan 17.
S. Costanzi, S. Neumann, and M. C. Gershengorn
Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects
J. Biol. Chem., June 13, 2008; 283(24): 16269 – 16273.
Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C 2006 Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175
Chu ZL, Jones RM, He H, Carroll C, Gutierrez V, Lucman A, Moloney M, Gao H, Mondala H, Bagnol D, Unett D, Liang Y, Demarest K, Semple G, Behan DP, Leonard J 2007 A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148:2601–2609