Chapter Sixteen - GPR119 Agonists for the Potential Treatment of Type 2 Diabetes and Related Metabolic Disorders
Introduction
The prevalence of diabetes mellitus has increased at an alarming rate in recent years, with an estimated 285 million people worldwide suffering from this serious chronic disease (International Diabetes Federation Diabetes Atlas, 2009). By 2030, this number is projected to exceed 400 million, costing the world economy more than US$490 billion in healthcare expenditure. Sedentary lifestyles and the increased occurrence in obesity have additionally contributed to the predicted diabetes epidemic (Diamond, 2003, Hossain et al., 2007). Although diabetes is underreported as a cause of death, the associated secondary complications related to cardiovascular disorders, retinopathy, nephropathy, and neuropathy are often the leading cause of mortality.
The majority of diabetic patients (90–95%) have type 2 diabetes (T2D), which is characterized by high blood glucose levels (hyperglycemia) resulting from insulin resistance, defective insulin secretion (β-cell dysfunction), or hepatic glucose overproduction (Leahy, 2008, Stumvoll et al., 2005). Current pharmacological treatments fall into three major categories: drugs that improve insulin sensitivity, drugs that increase insulin secretion from β-cells in a glucose-independent or glucose-dependent fashion, and insulin replacement (Ashiya & Smith, 2007, Levetan, 2007, Stumvoll et al., 2005). The first-line drugs include the insulin-sensitizing agent metformin and the glucose-independent insulin-releasing agents such as sulfonylureas and meglitinide analogs. Although both the classes of drugs effectively lower HbA1c and are heavily prescribed, they do not produce durable improvements in disease progression. In addition, sulfonylureas carry the side effects of hypoglycemia and weight gain. The peroxisome proliferator activator receptor gamma (PPARγ) agonist class of insulin sensitizers (thiazolidinediones; TZDs) is the most prescribed after metformin and sulfonylureas. TZDs display robust efficacy but are associated with weight gain, congestive heart failure, and fractures; death due to cardiovascular events has been suggested with rosiglitazone, but the data are currently inconclusive (Nissen and Woslki, 2007). Alpha-glucosidase inhibitors, agents that work by inhibiting the breakdown of carbohydrate to glucose in the intestine, are only modestly effective and produce GI side effects. Although insulin is associated with weight gain and hypoglycemia, there is increasing acceptance of its use as a second medication in addition to metformin in subjects with an A1c level > 8.5% (Nathan et al., 2009).
The gastrointestinal hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are released in response to ingestion of food, stimulate insulin secretion in a glucose-dependent manner (Drucker, 2007). Strategies involving GIP have received relatively less attention, primarily due to the decreased GIP responsiveness in T2D patients (Vilsbøll et al., 2002). On the other hand, approaches focused on exerting a pharmacological GLP-1 effect have resulted in the recent introduction of a new class of drugs that targets GLP-1 or its receptor (Drucker et al., 2010). These agents enhance glucose-dependent insulin secretion (GDIS) by direct agonism of the GLP-1 receptor (GLP-1 mimetics; e.g., exenatide, liraglutide) (Drucker and Nauck, 2006) or by preventing the breakdown of endogenously produced GLP-1 through selective inhibition of dipeptidyl peptidase IV (DPP-IV inhibitors; e.g., sitagliptin, vildagliptin, saxagliptin) (Ahrén, 2008, Brubaker, 2007). Both GLP-1 mimetics and DPP-IV inhibitors provide effective lowering of HbA1c and present a significantly low risk of hypoglycemia.
In addition to stimulating GDIS, GLP-1 has been shown to suppress glucagon secretion, delay gastric emptying, and decrease appetite (Drucker & Nauck, 2006, Gutniak et al., 1992). Activation of GLP-1 receptors has also been shown to enhance β-cell proliferation in rodents and to inhibit β-cell apoptosis in rodent and human islets (Baggio & Drucker, 2006, Brubaker & Drucker, 2004, Farilla et al., 2003). While the identification of orally active small-molecule GLP-1 agonists continues to remain challenging, strategies complementary to DPP-IV inhibitors that are based upon enhancing GDIS via stimulation of incretin hormone release have emerged as a promising approach in the treatment of diabetes. Furthermore, the use of a GLP-1 secretagogue in combination with DPP-IV inhibition may not only provide improved glycemic control, but also induce weight loss, a feature observed with GLP-1 mimetics but not with DPP-IV inhibitors. Several nonpeptide binding G protein-coupled receptors (GPCRs) have been deorphanized recently and are currently being evaluated as candidate GLP-1 secretagogues for T2D (Ahrén, 2009, Fyfe et al., 2007a, Mohler et al., 2009). Among these, the G protein-coupled receptor 119 (GPR119) has received considerable attention from the pharmaceutical industry in recent years (Fyfe et al., 2008a, Jones & Leonard, 2009, Jones et al., 2009, Overton et al., 2008, Shah, 2009). This review summarizes the research leading to the identification of GPR119 as a potential target for T2D and related metabolic disorders, and provides an overview of the recent progress made in the discovery of orally active GPR119 agonists.
Section snippets
GPR119 Receptor Expression
GPR119 is a class A (rhodopsin-like) GPCR originally identified through a bioinformatics approach (Fredriksson et al., 2003). The initial sequencing and signaling characteristics of this receptor were independently described by several research groups in the scientific and patent literature under various names (see Fyfe et al., 2008a). Although GPR119 belongs to the class A GPCR family, there is little overall sequence homology to other receptors. A phylogenetic analysis assigned GPR119 to the
GPR119 Signaling and Deorphanization
High-level expression of GPR119 in transfected HEK293 cells led to an increase in intracellular cAMP levels via activation of adenylate cyclase (Bonini et al., 2001, Bonini et al., 2002, Chu et al., 2007, Overton et al., 2006), indicating that this receptor couples efficiently to Gαs. Using this constitutively active GPR119-expressing cell line, Chu et al. (2007) failed to observe increases in inositol phosphate with or without coexpression of a Gαq/Gαi chimera, suggesting that GPR119 exhibits
GPR119 Agonism and Glucose Homeostasis
The distribution of GPR119 has implicated a role in glucose homeostasis and feeding behavior/satiety. Mice null for GPR119 are viable and appear to develop and reproduce normally. Consistent with the effects of GPR119 signaling on GLP-1 release in vitro, gpr119−/− mice have been shown to display lower plasma GLP-1 [7–36]amide levels in the postprandial state and after an oral glucose load (Chu et al., 2008, Lan et al., 2009). Additionally, GPR119 null mice maintained on a low fat (10% of kcal)
GPR119 Agonists: Medicinal Chemistry
The emerging interest in investigating the therapeutic potential of orally active GPR119 agonists is exemplified by the multitude of patent applications that have appeared in recent years (see Jones & Leonard, 2009, Jones et al., 2009, Shah, 2009). Based on the available structure–activity relationship (SAR) data, most GPR119 agonists can be viewed as containing two important pharmacophores: an aryl or heteroaryl moiety substituted with a hydrogen-bond accepting group, and a piperidine moiety
Conclusions
The combined stimulation of insulin and incretin release observed with GPR119 agonists provides a unique opportunity to regulate glucose homeostasis in patients with T2D. The glucose-dependent mechanism of these agents differentiates them from the sulfonylureas and insulin, which are associated with a high risk of hypoglycemia. Orally available GPR119 agonists also present an advantage over the currently available GLP-1 mimetics which suffer from the necessity of parenteral administration.
Acknowledgments
The authors thank Drs. Craig Boyle, Samuel Chackalamannil, William Greenlee, and Andrew Stamford for their valuable inputs in the preparation of this chapter.
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