GPR40 Receptor Agonists for the Treatment of Type 2 Diabetes and Related Diseases.

Abstract

The invention in this patent application relates to novel indanylaminopyridylcyclopropanecarboxylic acid derivatives, represented generally by formula I. These compounds are agonists of the G-protein coupled receptor 40 (GPR40) and may provide a useful treatment of metabolic diseases, such as type 2 diabetes mellitus, as well as conditions associated with this disease, including insulin resistance, obesity, cardiovascular disease, and dyslipidemia. Metabolic diseases may be classified as either congenital (caused by an inherited enzyme abnormality) or acquired (caused by a diseased endocrine organ or a failed metabolically important organ such as the liver or the pancreas). Diabetes mellitus is a metabolic disease, which is defined as a chronic hyperglycemia associated with consequential damages to organs and dysfunctions of metabolic processes. Diabetes mellitus Type 1 (a.k.a. insulin-dependent diabetes mellitus, IDDM) is a common disease in young people under 20 years of age. It is believed to be caused by an autoimmune disorder that leads to an insulitis and subsequent destruction of the beta cells of the islets of Langerhans, which are responsible for the insulin synthesis. This causes low production of insulin and results in elevated blood glucose levels (hyperglycemia). Diabetes mellitus Type 2 is common in older people. It is associated with a resistance to insulin in the liver and the skeletal muscles, and defective islets of Langerhans. Elevated blood glucose levels (and also high blood lipid levels) in diabetes patients can lead to the impairment of the functions of beta cells and to an increase in beta cells apoptosis. Current antidiabetic drugs exert little control on the levels of blood sugar and cannot prevent the occurrence of high and low blood sugar levels. Wide variations in blood sugar levels have toxic effects and may cause long-term complications in diabetes patients such as retinopathy, renopathy, neuropathy, and peripheral vascular disease. In addition, diabetes patients are at risk from other related conditions, such as obesity, hypertension, stroke, heart disease, and hyperlipidemia. Metabolic syndrome is a term that refers to a group of five risk factors, namely, abdominal obesity, high triglycerides, high blood pressure, high blood sugar, and low high-density lipoprotein (HDL). These factors are known to increase the risk of occurrence of type 2 diabetes and cardiovascular disease. A patient suffering from at least three of these factors is diagnosed with metabolic syndrome. The control of the levels of lipid and glucose in the blood is an essential part of treating type 2 diabetes, heart disease, and the metabolic syndrome risk factors. The G-protein coupled receptor 40 (GPR40), also named free fatty acid receptor 1 (FAA1), is a cell-surface receptor and a member of the gene superfamily of G-protein coupled receptors (GPCR). It was first identified as an orphan receptor (a receptor without a known ligand). GPR40 is highly expressed in the pancreatic beta cells and insulin-secreting cell lines. It is also expressed in enteroendocrine cells, taste cells, immune cells, splenocytes, and the brain. The endogenous ligands for GPR40 are fatty acids. GPR40 is activated especially by long-chain fatty acids, particularly oleic acid. The activation of GPR40 is linked primarily to the modulation of the Gq family of intracellular signaling G proteins and concomitant induction of elevated calcium levels, although activation of Gs- and Gi-proteins to modulate intracellular levels of cAMP have also been reported. Researchers have discovered that activation of GPR40 receptors by fatty acids in the insulin secreting cells causes elevation of the levels of insulin in the plasma. This discovery suggests that GPR40 agonists can potentially provide a treatment of type 2 diabetes by increasing insulin release. In addition, the use of GPR40 agonists can potentially restore and/or preserve the islet functions; therefore, they may be beneficial in delaying or preventing the diminution and loss of islet functions in Type 2 diabetic patients. This is a clear advantage over the current type 2 diabetes drugs, which can cause a gradual loss of islet activities over long-term use leading to the eventual dependence of patients on daily insulin injections to control their levels of blood sugars. Incretins are metabolic hormones, which are secreted by endocrine cells located in the epithelium of the small intestine as a result of increased glucose concentration in the lumen of the digestive tract. Incretins act to stimulate the secretion of insulin from pancreatic beta cells of the islets of Langerhans and can be deactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for incretin degradation. Related studies have identified a major role for the modulation of GPR40 in the secretion of several incretins such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), the gastric inhibitory peptide [also known as glucose-dependent insulinotropic polypeptide (GIP)], peptide YY (PYY), and possibly others, from the enteroendocrine cells. The above findings suggest that GPR40 agonists can potentially contribute to enhancing the level of insulin release in two different ways: i. Directly by stimulating the pancreatic beta cells. ii. Indirectly by the synergistic effect of elevated plasma levels of the incretin GLP-1 (and possibly GIP) on the insulin release. This indirect effect may be amplified by coadministration of inhibitors of DPP-4. Therapeutic agents that act as agonists of GPR40 are known in the art and could potentially be useful for the treatment of type 2 diabetes as well as conditions associated with that disease, including insulin resistance, obesity, cardiovascular disease, and dyslipidemia. The GPR40 agonists of formula I described in this patent application provide several advantages over other agonists such as enhanced potency, high metabolic and/or chemical stability, high selectivity and tolerability, and enhanced water solubility.