Robert M. Jones is currently Senior Director of Medicinal Chemistry at Arena Pharmaceuticals and also serve as Adjunct Faculty to the University of Mississippi, Department of Medicinal Chemistry. He has been an active medicinal chemistry researcher for the past 16 years, 13 of which have been in industry. Over the past 8 years his research has focused on metabolic diseases in particular Type 2 Diabetes. His work has led to several compounds entering or being nominated for clinical development, including a first in class GPR119 agonist for T2D. He has also been cited as an inventor of ~ 63 patents / provisional filings; and has published ~ 60 manuscripts and abstracts in the field of medicinal chemistry.

New Therapeutic Strategies for Type 2 Diabetes

Small Molecule Approaches

By Robert M. Jones

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-414-1

Contents

Chapter 1 Type 2 Diabetes: Disease Overview Daniel M. Kemp, 1,
Chapter 2 Marketed Small Molecule Dipeptidyl Peptidase IV (DPP4) Inhibitors as a New Class of Oral Anti-Diabetics Zhonghua Pei, 15,
Chapter 3 SGLT2 Inhibitors in Development William N. Washburn, 29,
Chapter 4 Glucokinase Activators in Development Kevin J. Filipski, Benjamin D. Stevens and Jeffrey A. Pfefferkorn, 88,
Chapter 5 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development James S. Scott and Jasen Chooramun, 109,
Chapter 6 Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity Rongjun He, Li-Fan Zeng, Yantao He and Zhong-Yin Zhang, 142,
Chapter 7 Recent Advances in the Discovery of GPR119 Agonists Unmesh Shah, Scott Edmondson and Jason W. Szewczyk, 177,
Chapter 8 Acyl-CoA:Diacylglycerol Acyltransferase-1 Inhibition as an Approach to the Treatment of Type 2 Diabetes Robert L. Dow, 215,
Chapter 9 Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver Gang Liu, 249,
Chapter 10 TGR5 Agonists in Development Antonio Macchiarulo, Antimo Gioiello and Roberto Pellicciari, 270,
Chapter 11 The Discovery and Development of MB07803, a Second-Generation Fructose-1,6-bisphosphatase Inhibitor with Improved Pharmacokinetic Properties, as a Potential Treatment of Type 2 Diabetes Qun Dang, Paul D. van Poelje and Mark D. Erion, 306,
Chapter 12 Inhibition of Glycogen Phosphorylase as a Strategy for the Treatment of Type 2 Diabetes Brad R. Henke, 324,
Chapter 13 SIRT1 Activators in Development Robert B. Perni, Vipin Suri, Thomas V. Riera, Joseph Wu, Charles A. Blum, George P. Vlasuk and James L. Ellis, 366,
Chapter 14 Long-Chain Free Fatty Acid Receptor Agonists Jonathan B. Houze, 403,
Chapter 15 Glucagon Receptor Antagonists in Development Duane E. DeMong and M. W. Miller, 429,
Chapter 16 ACC Inhibitors in Development Matthew P. Bourbeau, 464,
Subject Index, 501,

CHAPTER 1

Type 2 Diabetes: Disease Overview

DANIEL M. KEMP

Diabetes & Endocrinology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065, USA

E-mail: daniel.kemp@merck.com

1.1 Type 2 Diabetes

1.1.1 Societal and Economic Effects

Type 2 diabetes is a metabolic disease, and is characterized by elevated circulating glucose, otherwise known as hyperglycemia. The specific molecular cause of type 2 diabetes remains unknown, though considerable progress has been made to define the metabolic characteristics of people who have, or later acquire, the disease. What we are certain of is that two essential components define the overall metabolic dysfunction in type 2 diabetes; firstly, a relative insensitivity of glucose-utilizing tissues to insulin (i.e., skeletal muscle, liver, and adipose tissue), subsequently compounded by a relative insufficiency of insulin production from the pancreas, leading to whole body glucose intolerance. This progressive phenotype of insulin resistance and glucose intolerance contrasts with that of type 1 diabetes, which results from autoimmune destruction of insulin-producing β-cells of the pancreas, and thus is predominantly characterized by insulin insufficiency alone, and is treated specifically by injection of exogenous insulin.

In adults, type 2 diabetes accounts for about 90–95% of all diagnosed cases of diabetes, and develops most often in middle-aged and older adults. Among U.S. residents aged 65 years and older, 10.9 million, or 26.9%, had diabetes in 2010, according to the NIDDK. The total number of cases in the US alone is forecast to double from 24 million in 2009 to 44 million in 2034. Not surprisingly, in association with the growing diabetic population, spending on diabetes and related complications are projected to triple in the same period, from $100 billion in 2009 to around $300 billion in 2034. A report published in 2011 that included a dataset of 2.7 million individuals across the world concluded that diabetes prevalence is projected to be in the region of 347 million people. These staggering statistics outline the emerging epidemic of type 2 diabetes, and strongly indicate the need for new and better therapies.

1.1.2 Epidemiology

Though still poorly understood, the root cause of type 2 diabetes clearly results from interplay between genetic and environmental factors. The importance of genetics for the development of type 2 diabetes has long been recognized, both at the individual level (family history) and at the population level (ethnic background). For example, the most convincing evidence of genetic predisposition at the level of the individual comes from twin studies. Concordance rates for identical twins range from 70% up to close to 90%, with lifelong follow-up, and are higher than non-identical twins, siblings, or other family members. With respect to population genetics, strong evidence comes from studies like the San Antonio Heart Study, which focused on studying populations with different genetic backgrounds living in the same environment. In that study, the prevalence of type 2 diabetes was higher in Mexican Americans than in non-Hispanic whites at each level of obesity. Despite the overwhelming evidence that susceptibility for type 2 diabetes is inherited, the specific susceptibility genes and their mode of inheritance have yet to be determined, and this has been an area of intense research over the past decade. Though some monogenic traits have been firmly associated with a subset of type 2 diabetes patients, annotated as MODY genes (maturity onset diabetes of the young), the advent of genome-wide association studies, enabled by the human genome project, heralded the potential to identify disease-causing genes via the association of specific genetic mutations with incidences of type 2 diabetes. To date more than 50 genetic loci have been discovered, and these loci appear to associate predominantly with genes involved in pancreatic islet function, with few if any involved in insulin resistance-related pathways. Though initially surprising to some, this observation makes sense, as the primary cause of hyperglycemia is the inability of the pancreas to maintain sufficient insulin levels to drive glucose uptake into peripheral tissues. As mentioned earlier, although insulin resistance is a primary cause of the disease, type 2 diabetes only manifests when the β-cells of the pancreas fail to keep pace with demand. Mutations in genes that result in functional impairment of pancreatic β-cells are therefore most apparent in population genetics studies with hyperglycemia as the primary clinical endpoint. More recent genetic studies that focus on markers of insulin resistance are currently ongoing, and should identify additional genes involved more specifically in the function of insulin action and glucose utilization. It is highly anticipated that the results of these genetic studies should identify putative drug targets for the treatment of both insulin resistance and type 2 diabetes.

Environmental factors that influence the prevalence of type 2 diabetes can be easily exposed by studies focused on migrant populations. For example, Japanese migrants in Hawaii and Los Angeles are two to three times more likely to suffer type 2 diabetes than Japanese living in Japan. Such a shift in environmental influences over just one or two generations can impart surprisingly rapid changes in prevalence and incidence of type 2 diabetes. Factors such as birth weight, in utero exposure to diabetes, diet, obesity, and physical activity can expose an underlying genetic susceptibility within specific ethnic populations. The Pima Indians of Arizona are particularly notable with respect to their genetic predisposition to type 2 diabetes, clearly exposed by environmental factors of “western lifestyle”. All of these specific examples speak to the broader context of how exposure to an ever evolving global economy and cultural environment has unveiled the apparent fragility of the human genome, and underscores how habitat is just as important as evolution in defining what species thrive and perish.

1.1.3 Pathophysiology

The ability of insulin to stimulate glucose disposal has been extensively studied, and abundant evidence exists to confirm that insulin action is markedly decreased in patients with type 2 diabetes. The major route of glucose disposal, demonstrated by infusion studies, is uptake into the skeletal muscle, and it is reasonable to conclude that the majority of patients with type 2 diabetes have a defect in insulin-stimulated glucose disposal into muscle. However, it is also clear that impaired insulin-dependent glucose uptake per se cannot account for the development of hyperglycemia in patients with type 2 diabetes, because relatively normal fasting plasma glucose levels are often observed in individuals who are equally insulin resistant as patients with frank diabetes. Indeed, type 2 diabetes will develop only when insulin-resistant subjects are incapable of secreting sufficient insulin to compensate for the defect in skeletal muscle insulin action. To further elaborate, as fasting hyperglycemia develops only when the pancreas fails, the consequence of this decline in insulin secretory capacity must be defined further in order to understand the pathophysiology of type 2 diabetes. We need to consider the involvement of adipose tissue as an important player in the overall characterization of the disease. This is because resistance to insulin regulation at the level of the adipose tissue, or as a result of decreased insulin secretion, leads to elevated plasma free fatty acid (FFA) concentrations. Indeed, ambient plasma FFA concentrations are elevated in type 2 diabetes, and the greater the increase in FFA concentration, the higher the plasma glucose concentration. Exacerbation of the dysmetabolic state then ensues because elevated FFA levels decrease insulin-stimulated glucose uptake, cause lipotoxicity at the level of the pancreatic b-cell, and further compromises insulin secretory function. Furthermore, elevated FFA levels stimulate gluconeogenesis in the liver, decreasing the ability of hyperglycemia to suppress hepatic glucose production, further compounding the problem. To summarize, when insulin resistance is compensated by hyperinsulinemia, whole body glucose homeostasis can be preserved. But, when the insulin secretory response declines to a point where circulating plasma FFA levels become significantly elevated, the plasma glucose concentration increases precipitously due to unsuppressed hepatic glucose output, exacerbation of pancreatic b-cell failure, and impaired insulin-dependent glucose disposal into muscle.

Although far from complete, this high level perspective of the pathophysiology of type 2 diabetes serves to highlight complex interactions between carbohydrate and fat metabolism, and between the function of multiple metabolically active tissues of the body. This is underscored by the fact that many therapeutic approaches, including those discussed in this book, target diverse mechanisms within different tissues. The repertoire of drug targets presented here aim to regulate glucose metabolism either directly or indirectly via various compensatory mechanisms.

1.1.4 Etiology

As inferred already, there are many factors that can potentially give rise to, or exacerbate, type 2 diabetes, including obesity, hypertension, and elevated cholesterol. Others include aging, high-fat diets, and an inactive lifestyle. All of these causal factors are to some degree a result of our evolving environment. The onset of type 2 diabetes has traditionally been most common in middle age and later life, although it is now being more frequently seen in adolescents and young adults due primarily to the increase in child obesity and inactivity, and this aspect is worth further consideration as a defining component of type 2 diabetes, along with implications to therapeutic intervention.

A key etiological factor linking obesity to type 2 diabetes is insulin resistance, characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in fat and muscle. The physiological mechanisms connecting obesity to insulin resistance have received intense attention in recent years resulting in the emergence of several hypotheses to explain this link, such as (1) ectopic lipid accumulation in liver and muscle secondary to obesity-associated increase in serum free fatty acids, (2) altered production of various adipocyte-derived factors (collectively known as adipokines), and (3) low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system. However, not all obese individuals are insulin resistant, and in fact insulin sensitivity has been shown to vary up to six fold in this population, highlighting the importance of identifying genetic and environmental factors that place obese individuals at the greatest risk of obesity-related complications.

The degree to which obesity is affecting westernized society is worth noting, as it underlies the prevalence of type 2 diabetes, and serves as a leading indicator for metabolic dysfunction. In 2010, no U.S. state had a prevalence of obesity less than 20%. Thirty-six states had a prevalence of 25% or more; 12 of these states (Alabama, Arkansas, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Oklahoma, South Carolina, Tennessee, Texas, and West Virginia) had a prevalence of 30% or more. By comparing these statistics with those from 1990, the explosion in obesity rate is striking, and is depicted in Figure 1.1. The data strongly suggest that prevention (or reversal) of obesity would have a profound effect on the prevalence of type 2 diabetes. As such, many companies have focused their research on anti-obesity programs as a means to treating obesity-related metabolic diseases such as diabetes.

1.2 Treatment of Type 2 Diabetes

1.2.1 Lifestyle Management

Diet and exercise are the most powerful means to lower blood glucose levels in type 2 diabetes patients and are the foundation of effective treatment and disease management. Patient education and self-care practices are important aspects of disease management that help people with diabetes lead normal lives. In fact, the Diabetes Prevention Program (DPP), a large prevention study of people at high risk for diabetes, showed that lifestyle intervention to lose weight and increase physical activity reduced the development of type 2 diabetes by 58% during a 3-year period. The reduction was even greater, 71%, among adults aged 60 years or older. However, due mainly to socio- economic factors that have become a global concern, and inadequate compliance, diet and exercise alone appear insufficient to stem the epidemic of type 2 diabetes. As such, therapeutic drug intervention is a key component of any strategy to treat diabetes patients, and this book serves to introduce some of the primary therapeutic targets and drug discovery efforts that will likely add much needed strength to the physician’s armory.

1.2.2 Surgical Intervention

Although the management and prevention of diabetes through lifestyle modifications and weight loss represents the ideal therapy in appropriate candidates, supported by results from the DPP and the Finnish Prevention Study, over 95% of patients not participating in a prevention research study are unable to achieve and maintain any significant weight loss over time. Robust and sustained weight loss following bariatric surgery is an emerging therapeutic option for severely obese subjects, especially when obesity is complicated by diabetes or other co-morbidities. The two most common types of procedures currently used in the U.S. are adjustable gastric bands and Roux-en-Y gastric bypass (RYGB), and these procedures can be performed laparoscopically, further reducing the perioperative morbidity and mortality associated with the surgery. While the RYGB procedure usually results in greater sustained weight loss (40–50%) than adjustable gastric banding (20– 30%), it also carries greater morbidity and nutritional/metabolic issues, such as deficiencies in iron, B12, calcium, and vitamin D. Following RYGB, most subjects experience improvements in diabetes control, hypertension, dyslipidemia, and other obesity-related conditions. In patients with impaired glucose tolerance most studies report 99–100% prevention of progression to diabetes, while in subjects with diabetes prior to surgery, resolution of the disease is reported in 65–90% of the cases. While improvements in insulin resistance and β-cell function are related to surgically induced weight loss, the rapid postoperative improvement in glycemia is possibly due to a combination of decreased nutrient intake and changes in gut hormones independent of weight loss.

Regulatory authorities around the world are now seriously discussing whether gastric bypass surgery should be used specifically to treat type 2 diabetes in non-obese patients, and concerted research efforts are being pursued to test less-invasive procedures that may mimic the profound glucose regulatory effects of RYGB. Time will tell whether the efficacy and long- term cost-effectiveness of bariatric surgery will offset the safety and tolerability issues that exist currently.

1.2.3 Current Drug Therapy Options

The relevance of this book is shown by the fact that the standard of care for treatment of type 2 diabetes in the US has not changed meaningfully in over 15 years. One reason for this is the entrenched first- and second-line add-on options that are generic and therefore inexpensive, i.e., metformin and the sulfonylureas. However, despite the established landscape, there remains significant unmet need in glycemic control, and especially so now that several branded drug classes have failed to gain sustained acceptance due to a variety of issues, including tolerability, dosing, and safety. That said, the newest classes of approved drugs, the incretin (GLP-1) based therapies, have made significant inroads into the second-line and 3rd add-on positions. However, these drugs are yet to take a majority share in the market and are somewhat limited in the degree of efficacy attained in the clinic. The portfolio of currently approved small molecule drug classes is presented in Table 1.1.

(Continues…)Excerpted from New Therapeutic Strategies for Type 2 Diabetes by Robert M. Jones. Copyright © 2012 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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