Trends in Drug Discovery in Diabetes and Obesity

Series Editor’s Preface xi

Preface xiii

1 The Role of Gut Peptides in the Regulation of Body Weight 1

Jens J. Holst and Sten Madsbad

Introduction and Methodological Considerations 1

Mimicry 2

Hormone Antagonists 3

Activation and Inactivation 3

Somatostatin as a Tool 4

Gut Hormones with a Possible Role in Food Intake 5

Cholecystokinin 5

GLP-1 7

Role of Endogenous GLP-1 in Food Intake Regulation 8

Mechanism of Action of Exogenous GLP-1 Receptor Agonists 9

Development of GLP-1 Receptor Agonists for Obesity Therapy 9

Oxyntomodulin and Glucagon-GLP-1 Coagonists 10

PYY 11

GIP 13

Ghrelin 16

Conclusion 18

References 19

2 Agonists and Antagonists of the Human GIP Receptor 33

Hüsün S. Kizilkaya, Larke S. Gasbjerg, Jens J. Holst, and Mette M. Rosenkilde

Introduction 33

Objective of the Chapter 34

Background 35

Glucose-Dependent Insulinotropic Polypeptide – Rationale for Initial Therapeutic Interest 35

GIP – Posttranslational Processing, Secretion, and Degradation 36

Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) 37

Receptor Activation and Signaling 37

Desensitization, Internalization, and Receptor Trafficking 40

Expression in Humans and Animals 45

Important Species Differences in the GIP System 45

Physiological Actions of GIP 46

GIP’s Effect on the Pancreas of Healthy Individuals 46

GIP’s Effect on the Pancreas of Individuals with Type 2

Diabetes 47

GIP’s Effect on the Pancreas of Individuals with Obesity 48

Extrapancreatic Physiological Effects of GIP 49

Adipose Tissue 49

BodyWeight 50

Energy Expenditure 51

Cardiovascular System 51

Bones 52

Central Nervous System 53

Pharmacological GIPR Agonism 54

Animal Studies 54

Human Studies 55

Pharmacological GIPR Antagonism 60

Animal Studies 60

Human Studies 61

Theories Bridging GIPR Agonism and Antagonism 62

Conclusion 63

References 64

3 Amylin – Biological Aspects 87

Thomas A. Lutz

Introduction 87

Amylin Synthesis and Secretion 87

Different Molecular Forms of Amylin 88

Amylin Signaling at the Amylin Receptor 88

Amylin Receptor Activation and Intracellular Signaling 88

Amylin’s Effect on Energy Homeostasis 89

Amylin Effects on Eating; Induction of Satiation 89

Amylin Effects on Energy Expenditure 90

Sex Differences in Amylin Action 91

Brain Sites of Amylin Action 91

Caudal Hindbrain with the AP and the NTS 91

Projections from the AP – Role of the Lateral Parabrachial Nucleus 92

Single Cell Studies to Define the Phenotype of Caudal Hindbrain Neurons Involved in Amylin Action 93

Other Brain Areas Mediating the Actions of Amylin 94

Direct Amylin Action in the Hypothalamus 94

Central Reward Processing of Amylin in the Ventral Tegmental Area (VTA), the Nucleus Accumbens (NAc), the Dorsal Tegmental Area, and the Medial Prefrontal Cortex 95

Amylin–Leptin Interactions in the Regulation of Energy Homeostasis 96

Amylin–Leptin Interactions in the AP and NTS 97

Amylin–Leptin Interactions in the VMH (ARC+VMN) 98

Amylin–Leptin Interactions in the VTA 98

Other Molecular Forms of Amylin and Their Potential Role in

Physiology and Pathophysiology 99

Amylin Forms 99

Amylin Analogs Mimic Amylin’s Effects on Eating 100

Amyloid Formation in Pancreatic Islets 102

Mechanisms of Amyloid Genesis 102

Pathological Effects of Amylin Deposits on Pancreatic ß-Cells 103

Therapeutic Approach to Reduce Amylin-Derived Fibrillogenic 103

Conclusion 104

Acknowledgments and Disclosures 104

References 105

4 Peptide-Based GLP-1 Receptor Agonists for the Treatment of Type 2

Diabetes and Obesity 121

János T. Kodra, Lars Linderoth, Steffen Reedtz-Runge, Thomas Kruse, and Jacob C. Kofoed

Introduction 121

GLP-1 Biology 122

GLP-1 Receptor Binding and Activation 123

Clinical Relevant Peptide GLP-1 Receptor Agonists 124

Exendin-4-Based Analogs 124

Exenatide 124

Exenatide Long-Acting Release (LAR) 125

Lixisenatide 126

Efpeglenatide 126

Loxenatide 127

Noiiglutide 127

Visepegenatide 128

GLP-1-Based Analogs 128

Liraglutide 128

Semaglutide 129

Taspoglutide 129

Albiglutide and Albenatide 130

Dulaglutide 131

Ecnoglutide 131

Utreglutide 132

HyGlutide 132

ZT002 133

Bofanglutide 133

Summary and Outlook 134

References 134

5 Oral Agents Used to Treat Type 2 Diabetes and Obesity 141

John Liddle, Ekaterina Ratkova, Cátia A. Bonito, Christopher J. Rhodes, and Sarah Will

Introduction 141

Type 2 Diabetes Oral Agents 141

Sulfonylureas 145

Biguanides 146

Alpha-Glucosidase Inhibitors 147

Meglitinides (Glinides) 147

Thiazolidinediones 148

Dipeptidyl Peptidase-4 (DPP4) Inhibitors 150

Bile Acid Sequestrants 150

Dopamine-2 Agonists 152

Sodium-Glucose Transporter-2 (SGLT2) Inhibitors 153

Glimins 154

Other (Non-Approved) Small Molecule T2D Treatments 154

Obesity Oral Agents 154

Nicotine 155

Thyroxine 155

Dinitrophenol 158

Amphetamines 159

Centrally-Acting Combinations 159

Lorcaserin 161

Orlistat 162

Cannabinoid Receptor Antagonists 162

ß3-Adrenoreceptor Agonists 163

Melanocortin 4 Receptor (MC4R) Agonist 163

A Current Perspective for Oral Diabetes and Obesity Small Molecules 164

Small Molecule Glucagon-Like Peptide 1 Receptor (GLP-1R) Agonists 164

Introduction 164

The First Reported Small Molecule GLP-1R Agonists 165

GLP-1R Agonists and Positive Allosteric Modulators 168

Small Molecule GLP-1R Agonists in Clinical Development 173

TTP273 from vTv Therapeutics 173

Danuglipron and Lotiglipron 173

Orforglipron 176

Summary of the GLP-1R Small Molecule Agonist Landscape 179

Outlook for GLP-1R Small Molecule Agonists and

Beyond 180

References 180

6 Trends in the Field of Insulin Drug Design 197

Thomas Hoeg-Jensen

Introduction 197

Native Insulin 198

Meal Insulin Designs and Formulations 199

Once-Daily Basal Insulin Designs 199

Once-Weekly Insulin Designs 201

Tissue Selective and Functionally Selective Insulin 203

Oral and Pulmonary Insulin 204

Glucose-Sensitive Insulin 204

Insulin Pumps and Cell-Based Therapy 206

Conclusions 206

Abbreviations 207

Biography 207

References 207

7 Neuropeptide Y Receptor Ligands and Opportunities Within Diabetes

and Obesity 215

Soren Ostergaard

The Neuropeptide Y (NPY) Peptide and Receptor Family 215

Neuropeptides NPY, PYY, and PP 215

NPY Receptors and Distribution 217

Knockout Studies in Rodents 218

Y1R/Y5R Agonism 219

Y1R/Y5R Antagonists for Diabetes or Obesity Treatment 220

PP and Y4R Interaction 222

PYY and Y2R Interaction 223

Regulator of Food Energy Homeostasis 223

Regulator of Glucose Homeostasis 224

Lessons from Bariatric Surgery Support the Critical Role of PYY 224

SAR and Y2R Selective Agonists 225

Half-Life Extension of PYY Analogs 226

Y2R Agonism and Combinations with Other Peptide Agonists 227

Human Studies and Trials with PYY and Analogs 229

Prospects of Obesity and Diabetes Treatment with PYY 231

References 232

8 PrRP-GPR10 Signaling and Metabolism 243

Claire H. Feetham, Amy A. Worth, Sam Groom, and Simon M. Luckman

Modified PrRP Peptides as a New Pharmacological Tool 243

The Discovery of GPR10 and PrRP 244

Prolactin-Releasing Hormone – A Misnomer? 244

Central Metabolic Effects of PrRP 246

Receptor Coupling and Distribution 246

Prlh and Prlhr Knockout Mouse Models 248

Natural Polymorphisms in the PRLHR Gene 248

Genetic Mutations Affecting NPFF Signaling Related to

Metabolism 249

Brainstem PrRPNTS Neurons 250

Hypothalamic PrRPDMH Neurons 252

Systemically Administered PrRP Analogs 252

Conclusions 253

References 254

9 The Becoming of Dasiglucagon 263

Ditte Riber, Jesper M. Mathiesen, Lise Giehm, Francesca Macchi, Mikael Elander, and Jesper S. Villadsen

The Becoming of Dasiglucagon 263

The Discovery of Glucagon and Its Physiological Effects 263

Medical Use of Glucagon as a Rescue Treatment for Insulin Induced Hypoglycemia in Diabetes Mellitus 264

Rational Design of Dasiglucagon 265

Basis for the Chemical and Physical Instability of Native Glucagon 265

Design Strategy and Assays 267

1st Design: Exploring Substitution of Residues Susceptible for Isomerization, Cleavage, and Oxidation 268

2nd Design: Exploring Substitution of Potential Deamidation Sites and Disruption of an Aggregation Prone Hydrophobic Region 268

3rd Design: Combining the Learnings from Previous SAR Rounds 270

4th Design 272

5th Design 274

Characterization of Dasiglucagon 279

Physical and Chemical Stability of Dasiglucagon 279

Rotation Study – Simulating Real Use by Patients 279

Structural Characterization by Circular Dichroism 280

Pharmacological Effect of Dasiglucagon in Humans 281

Conclusion 282

Amino Acid Abbreviations 283

References 284

Index 287