Patent Watch

October 29, 2012

These GPR119 modulators may help treat diabetes. Diabetes mellitus is a metabolic disease in which insulin deficiency elevates patients’ blood sugar. Type 1 diabetes makes up <10% of all diabetes cases; its insulin deficiency results from destruction of islet cells in the pancreas. The more common type 2 diabetes is caused by insulin resistance and relative insulin deficiency, which may be caused by reduced numbers of cellular insulin receptors, disruption of cellular signaling pathways, or both. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy, kidney failure, and poor blood circulation in limbs, which may lead to amputation.

Obesity is believed to be one of the primary causes of type 2 diabetes in people who are genetically susceptible to the disease. Whereas obesity is considered a critical risk factor for diabetes, how the accumulation of fat in some patients affects a pathological change in insulin secretion is still unknown.

There is no known cure for diabetes. Type 2 diabetes is initially managed by regular exercise and dietary modification. As it progresses, it is managed by medications and/or insulin. Standard medications for the disease focus on controlling blood glucose levels (see sidebar).

Despite the number of available medications, orally effective treatments for diabetes that effectively regulate glucose homeostasis and have improved safety profiles and reduced adverse effects are needed. F. Himmelsbach, E. Langkopf, and B. Nosse disclose compounds that modulate G-protein-coupled receptor GPR119, which is a promising target for treating diabetes, obesity, and other metabolic disorders.

GPR119 is expressed predominantly in pancreas β cells and in intestinal K and L cells. Recent results from in vitro and animal-model studies show that modulating GPR119 may produce favorable effects on glucose homeostasis (without the risk of hypoglycemia), food intake, body weight gain, and possibly β cell preservation.

Stimulating GPR119 increases the intracellular accumulation of cyclic adenosine monophosphate (cAMP) and leads to enhanced glucose-dependent insulin secretion from pancreatic β cells and to greater release of incretin hormones GLP-1, GIP (glucose-dependent insulinotropic peptide), and PYY (polypeptide YY). GPR119 can be activated by endogenous stimulants such as oleoylethanolamide and small-molecule agonists described by the inventors. Oral administration of small-molecule GPR119 agonists improves glucose tolerance in rodents and humans.

The inventors disclose compounds of formula 1 and their use as GPR119 modulators. They believe that these agonists may provide treatments for types 1 and 2 diabetes, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, high blood pressure, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction, and bone-related diseases (e.g., osteoporosis, rheumatoid arthritis, and osteoarthritis).

To determine the effect of the compounds on activating GPR119 and on stimulating intracellular cAMP concentrations, the inventors used the PerkinElmer AlphaScreen cAMP Assay Kit. They report EC50 values for all 94 examples of the invention. Compounds 2, 3, 5, and 6 had the lowest values (2–3 nM), and compound 4 had the highest (228 nM).

Increasing the levels of incretins GLP-1, GIP, and PYY by GPR119 stimulation may provide treatments for other disorders and diseases. GLP-1 receptor agonists protect against myocardial infarction and cognitive and neurodegenerative disorders. GIP activates osteoblastic receptors to promote collagen type I synthesis and alkaline phosphatase activity, both associated with bone formation.

PYY is associated with reduced food intake and body weight gain in rodent models. It acts as an agonist for the Y2R receptor to protect against inflammatory bowel disease and Crohn's disease. There are also reports that Y2R agonists such as PYY can suppress tumor growth in pancreatic cancer. (Boehringer Ingelheim GmbH [Ingelheim am Rhein, Germany]. WIPO Publication 2012098217, July 26, 2012; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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Main classes of diabetes drugs

  • Biguanide structures activate the enzyme AMP-activated protein kinase (AMPK), which plays a role in insulin signaling and glucose and fat metabolism. An example is metformin (Glucophage), the most-used type 2 diabetes medication.
  • Sulfonylurea insulin secretagogues inhibit the KATP channel of pancreatic β cells. Glimepiride (Amaryl) and other drugs in this class may induce hypoglycemia, weight gain, and increased risk of cardiovascular death.
  • Thiazolidinediones bind to the protein PPARγ, which regulates fatty acid storage and glucose metabolism. Examples are rosiglitazone (Avendia) and pioglitazone (Actos). Studies have linked some of these drugs to an increased risk of heart disease and stroke.
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors [e.g., sitagliptin (Januvia)] increase the blood concentration of the incretin glucagon-like peptide 1 by inhibiting its degradation. Sitagliptin and other DPP-4 inhibitors, however, may also influence the tissue levels of other hormones and peptides.
  • One FDA-approved drug, exanatide, a 39–amino acid polypeptide, is an agonist for incretin glucagon-like peptide 1 (GLP-1), which stimulates insulin secretion in the presence of high glucose. It must be injected because it is not orally bioavailable.
  • α-Glucosidase inhibitors are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They do not have a direct effect on insulin secretion or sensitivity but slow the digestion of starch in the small intestine. They may only be helpful in combination with other medications.
  • Sodium glucose transporter 2 (SGLT2) accounts for 90% of the glucose reabsorption in the kidneys. SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels independently of insulin concentration. Examples are the experimental drugs dapagliflozin and canagliflozin.