Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced by islet cells in the pancreas. Patients having Type 2 diabetes have a resistance to the effects of insulin. These patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as they compensate for the reduced effectiveness of insulin by secreting increased amounts of insulin (Polonsky, Int. J. Obes, Relat. Metab. Disord. 24 Suppl 2:S29-31, 2000). The beta cells within the pancreatic islets initially compensate for insulin resistance by increasing insulin output. Insulin resistance is not primarily caused by a diminished number of insulin receptors but rather by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle, and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver. Eventually, a patient may be become diabetic due to the inability to properly compensate for insulin resistance. In humans, the onset of Type 2 diabetes due to insufficient increases (or actual declines) in beta cell mass is apparently due to increased beta cell apoptosis relative to non-diabetic insulin resistant individuals (Butler et al., Diabetes 52:102-110, 2003).
Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease. Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, corollary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, effective therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Patients who have insulin resistance often exhibit several symptoms that together are referred to as Syndrome X or Metabolic Syndrome. According to one widely used definition, a patient having Metabolic Syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity, (2) hypertriglyceridemia, (3) low levels of high-density lipoprotein cholesterol (HDL), (4) high blood pressure, and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined clinically in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with Metabolic Syndrome, whether they have or develop overt diabetes mellitus, have an increased risk of developing the macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.
There are several available treatments for Type 2 diabetes, each of which has its own limitations and potential risks. Physical exercise and a reduction in dietary intake of calories often dramatically improves the diabetic condition and are the usual recommended first-line treatment of Type 2 diabetes and of pre-diabetic conditions associated with insulin resistance. Compliance with this treatment is generally very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat and carbohydrates. Pharmacologic treatments have largely focused on three areas of pathophysiology: (1) hepatic glucose production (biguanides such as phenformin and metformin), (2) insulin resistance (PPAR agonists such as rosiglitazone and pioglitazone), (3) insulin secretagogues (sulfonylureas such as tolbutamide, glipizide, and glimepiride); (4) incretin hormone mimetics (GLP-1 derivatives and analogs, such as exenatide and luraglitide); and (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, and alogliptin).
Recent research has focused on pancreatic islet-based insulin secretion that is controlled by glucose-dependent insulin secretion. This approach has the potential for stabilization and restoration of β-cell function. In this regard, research has been done on the affects of antagonizing one or more of the somatostatin receptors. Somatostatin (SST) is a cyclic tetradecapeptide hormone that is widely distributed throughout the body and exhibits multiple biological functions that are mostly inhibitory in function, such as the release of growth hormone, pancreatic insulin, glucagon, and gastrin.
SST hormone activity is mediated through SST-14 and SST-28 isoforms that differentially bind to the five different SST receptor subtypes (SSTR1-5). In humans SSTR1 and SSTR2 are found in the pituitary, small intestine, heart and spleen with SSTR2 predominately in the pancreas, pituitary and the stomach. SSTR3 and SSTR4 are found in the pituitary, heart, liver, spleen stomach, small intestine and kidney. SSTR5 is found in high concentration in the pituitary, as well as the pancreas. It has been shown that S-28 and S-14 bind with similar affinity to SSTR1, SSTR2, SSTR3, and SSTR4. The receptor SSTR5 can be characterized by its preferential affinity for S-28 (Chisholm et al., Am. J. Physiol Endocrinol Metab. 283:E311-E317 (2002)).
SSTR5 is expressed by human islet β cells that are responsible for producing insulin and amylin. Therefore, binding to the SSTR5 could affect insulin secretion. For example, by using in vitro isolated perfused pancreas preparations from 3-month-old mice, it was demonstrated that SSTR5 global knockout mice pancreata have low basal insulin production, but a near normal response to glucose stimulation. It was theorized that, since along with SSTR5, SSTR1 is also expressed in islet β cells up-regulated SSTR1 compensates for the loss of SSTR5 in young knockout mice. As the mice aged, however, SSTR1 expression decreased in both the knockout mice and the aged-control wild-type mice. With lower SSTR1 expression in vivo, SSTR5 knockout mice had increased basal and glucose stimulated insulin secretion due to near complete lack of SSTRs on the knockout mice islet β cells with subsequent loss of the inhibitory SST response (Wang et al., Journal of Surgical Research, 129, 64-72 (2005)).
The proximity of D cells producing S-28 and L-cells containing GLP-1 in the ileum suggest that S-28 acting through SSTR5 may additionally participate in the direct regulation of GLP-1 secretion. To determine if S-28 acting through SSTR5 participates in the direct regulation of GLP-1 secretion, fetal rat intestinal cell cultures were treated with somatostatin analogs with relatively high specificity for SSTR2-5. GLP-1 secretion was inhibited by an SSTR5-selective analog more potently that S-14 and nearly as effectively as S-28 (Chisholm et al., Am. J. Physiol Endocrinol Metab. 283:E311-E317, 2002). A selective antagonist of SSTR5 is anticipated to block the suppression of GLP-1 secretion by endogenous somatostatin peptides, thereby elevating circulating GLP-1 levels. Elevated endogenous GLP-1 levels are associated with beneficial effects in the treatment of Type 2 diabetes (Arulmozhi et al., European Journal of Pharmaceutical Sciences, 28, 96-108 (2006)).
US 2008/0293756 discloses 4,4 disubstituted piperidine derivatives as SST Receptor Subtype 5 antagonists useful to treat diabetes.
Small molecule SSTR antagonists are also disclosed in US 20080249101; WO 2008031735; WO 2008019967; WO 2006094682; WO 2006128803; WO 2007025897; WO 20070110340 and WO 2008000692.
Other small molecule and peptide SSTR antagonists known in the art are disclosed in Wilkinson et al., British Journal of Pharmacology 118, 445-447 (1996); Hocart et al., J. Med. Chem. 41, 1146-1154 (1998); Hay et al., Bioorg. Med. Chem. Lett. 11, 2731-2734 (2001), Martin et al., J. Med. Chem. 50, 6291-6295 (2007) and Guba et al., J. Med. Chem. 50, 6295-6298 (2007), Martin et al., Bioorg. Med. Chem. Lett. 19, 6106-6113 (2009), and Sprecher et al., Regulatory Peptides 159, 19-27 (2010).
Described herein are selective, directly acting SSTR5 antagonists, which are useful as therapeutically active agents for the treatment and/or prevention of diseases that are associated with the modulation of SSTR5. Diseases that can be treated or prevented with SSTR5 antagonists include diabetes mellitus, impaired glucose tolerance and elevated fasting glucose.
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