Trends in Drug Discovery in Diabetes and Obesity

Lars Linderoth, PhD, is a Director at Novo Nordisk, where he has managed multiple departments within research chemistry in Denmark. He has authored several publications and is named as inventor on several patents within the field of drug discovery, bringing direct industry perspective to this volume. Søren Østergaard, PhD, is a Principal Scientist at Novo Nordisk with extensive experience in peptide drug discovery. Previously holding an assistant professorship at The University of Copenhagen, he has authored more than 45 publications and is named as inventor on more than 20 patents.

• Series Editor’s Preface xiPreface xiii1 The Role of Gut Peptides in the Regulation of Body Weight 1Jens J. Holst and Sten MadsbadIntroduction and Methodological Considerations 1Mimicry 2Hormone Antagonists 3Activation and Inactivation 3Somatostatin as a Tool 4Gut Hormones with a Possible Role in Food Intake 5Cholecystokinin 5GLP-1 7Role of Endogenous GLP-1 in Food Intake Regulation 8Mechanism of Action of Exogenous GLP-1 Receptor Agonists 9Development of GLP-1 Receptor Agonists for Obesity Therapy 9Oxyntomodulin and Glucagon-GLP-1 Coagonists 10PYY 11GIP 13Ghrelin 16Conclusion 18References 192 Agonists and Antagonists of the Human GIP Receptor 33Hüsün S. Kizilkaya, Lærke S. Gasbjerg, Jens J. Holst, and Mette M. RosenkildeIntroduction 33Objective of the Chapter 34Background 35Glucose-Dependent Insulinotropic Polypeptide – Rationale for Initial Therapeutic Interest 35GIP – Posttranslational Processing, Secretion, and Degradation 36Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) 37Receptor Activation and Signaling 37Desensitization, Internalization, and Receptor Trafficking 40Expression in Humans and Animals 45Important Species Differences in the GIP System 45Physiological Actions of GIP 46GIP’s Effect on the Pancreas of Healthy Individuals 46GIP’s Effect on the Pancreas of Individuals with Type 2Diabetes 47GIP’s Effect on the Pancreas of Individuals with Obesity 48Extrapancreatic Physiological Effects of GIP 49Adipose Tissue 49BodyWeight 50Energy Expenditure 51Cardiovascular System 51Bones 52Central Nervous System 53Pharmacological GIPR Agonism 54Animal Studies 54Human Studies 55Pharmacological GIPR Antagonism 60Animal Studies 60Human Studies 61Theories Bridging GIPR Agonism and Antagonism 62Conclusion 63References 643 Amylin – Biological Aspects 87Thomas A. LutzIntroduction 87Amylin Synthesis and Secretion 87Different Molecular Forms of Amylin 88Amylin Signaling at the Amylin Receptor 88Amylin Receptor Activation and Intracellular Signaling 88Amylin’s Effect on Energy Homeostasis 89Amylin Effects on Eating; Induction of Satiation 89Amylin Effects on Energy Expenditure 90Sex Differences in Amylin Action 91Brain Sites of Amylin Action 91Caudal Hindbrain with the AP and the NTS 91Projections from the AP – Role of the Lateral Parabrachial Nucleus 92Single Cell Studies to Define the Phenotype of Caudal Hindbrain Neurons Involved in Amylin Action 93Other Brain Areas Mediating the Actions of Amylin 94Direct Amylin Action in the Hypothalamus 94Central Reward Processing of Amylin in the Ventral Tegmental Area (VTA), the Nucleus Accumbens (NAc), the Dorsal Tegmental Area, and the Medial Prefrontal Cortex 95Amylin–Leptin Interactions in the Regulation of Energy Homeostasis 96Amylin–Leptin Interactions in the AP and NTS 97Amylin–Leptin Interactions in the VMH (ARC+VMN) 98Amylin–Leptin Interactions in the VTA 98Other Molecular Forms of Amylin and Their Potential Role inPhysiology and Pathophysiology 99Amylin Forms 99Amylin Analogs Mimic Amylin’s Effects on Eating 100Amyloid Formation in Pancreatic Islets 102Mechanisms of Amyloid Genesis 102Pathological Effects of Amylin Deposits on Pancreatic β-Cells 103Therapeutic Approach to Reduce Amylin-Derived Fibrillogenic 103Conclusion 104Acknowledgments and Disclosures 104References 1054 Peptide-Based GLP-1 Receptor Agonists for the Treatment of Type 2Diabetes and Obesity 121János T. Kodra, Lars Linderoth, Steffen Reedtz-Runge, Thomas Kruse, and Jacob C. KofoedIntroduction 121GLP-1 Biology 122GLP-1 Receptor Binding and Activation 123Clinical Relevant Peptide GLP-1 Receptor Agonists 124Exendin-4-Based Analogs 124Exenatide 124Exenatide Long-Acting Release (LAR) 125Lixisenatide 126Efpeglenatide 126Loxenatide 127Noiiglutide 127Visepegenatide 128GLP-1-Based Analogs 128Liraglutide 128Semaglutide 129Taspoglutide 129Albiglutide and Albenatide 130Dulaglutide 131Ecnoglutide 131Utreglutide 132HyGlutide 132ZT002 133Bofanglutide 133Summary and Outlook 134References 1345 Oral Agents Used to Treat Type 2 Diabetes and Obesity 141John Liddle, Ekaterina Ratkova, Cátia A. Bonito, Christopher J. Rhodes, and Sarah WillIntroduction 141Type 2 Diabetes Oral Agents 141Sulfonylureas 145Biguanides 146Alpha-Glucosidase Inhibitors 147Meglitinides (Glinides) 147Thiazolidinediones 148Dipeptidyl Peptidase-4 (DPP4) Inhibitors 150Bile Acid Sequestrants 150Dopamine-2 Agonists 152Sodium-Glucose Transporter-2 (SGLT2) Inhibitors 153Glimins 154Other (Non-Approved) Small Molecule T2D Treatments 154Obesity Oral Agents 154Nicotine 155Thyroxine 155Dinitrophenol 158Amphetamines 159Centrally-Acting Combinations 159Lorcaserin 161Orlistat 162Cannabinoid Receptor Antagonists 162β3-Adrenoreceptor Agonists 163Melanocortin 4 Receptor (MC4R) Agonist 163A Current Perspective for Oral Diabetes and Obesity Small Molecules 164Small Molecule Glucagon-Like Peptide 1 Receptor (GLP-1R) Agonists 164Introduction 164The First Reported Small Molecule GLP-1R Agonists 165GLP-1R Agonists and Positive Allosteric Modulators 168Small Molecule GLP-1R Agonists in Clinical Development 173TTP273 from vTv Therapeutics 173Danuglipron and Lotiglipron 173Orforglipron 176Summary of the GLP-1R Small Molecule Agonist Landscape 179Outlook for GLP-1R Small Molecule Agonists andBeyond 180References 1806 Trends in the Field of Insulin Drug Design 197Thomas Hoeg-JensenIntroduction 197Native Insulin 198Meal Insulin Designs and Formulations 199Once-Daily Basal Insulin Designs 199Once-Weekly Insulin Designs 201Tissue Selective and Functionally Selective Insulin 203Oral and Pulmonary Insulin 204Glucose-Sensitive Insulin 204Insulin Pumps and Cell-Based Therapy 206Conclusions 206Abbreviations 207Biography 207References 2077 Neuropeptide Y Receptor Ligands and Opportunities Within Diabetesand Obesity 215Søren ØstergaardThe Neuropeptide Y (NPY) Peptide and Receptor Family 215Neuropeptides NPY, PYY, and PP 215NPY Receptors and Distribution 217Knockout Studies in Rodents 218Y1R/Y5R Agonism 219Y1R/Y5R Antagonists for Diabetes or Obesity Treatment 220PP and Y4R Interaction 222PYY and Y2R Interaction 223Regulator of Food Energy Homeostasis 223Regulator of Glucose Homeostasis 224Lessons from Bariatric Surgery Support the Critical Role of PYY 224SAR and Y2R Selective Agonists 225Half-Life Extension of PYY Analogs 226Y2R Agonism and Combinations with Other Peptide Agonists 227Human Studies and Trials with PYY and Analogs 229Prospects of Obesity and Diabetes Treatment with PYY 231References 2328 PrRP-GPR10 Signaling and Metabolism 243Claire H. Feetham, Amy A. Worth, Sam Groom, and Simon M. LuckmanModified PrRP Peptides as a New Pharmacological Tool 243The Discovery of GPR10 and PrRP 244Prolactin-Releasing Hormone – A Misnomer? 244Central Metabolic Effects of PrRP 246Receptor Coupling and Distribution 246Prlh and Prlhr Knockout Mouse Models 248Natural Polymorphisms in the PRLHR Gene 248Genetic Mutations Affecting NPFF Signaling Related toMetabolism 249Brainstem PrRPNTS Neurons 250Hypothalamic PrRPDMH Neurons 252Systemically Administered PrRP Analogs 252Conclusions 253References 2549 The Becoming of Dasiglucagon 263Ditte Riber, Jesper M. Mathiesen, Lise Giehm, Francesca Macchi, Mikael Elander, and Jesper S. VilladsenThe Becoming of Dasiglucagon 263The Discovery of Glucagon and Its Physiological Effects 263Medical Use of Glucagon as a Rescue Treatment for Insulin Induced Hypoglycemia in Diabetes Mellitus 264Rational Design of Dasiglucagon 265Basis for the Chemical and Physical Instability of Native Glucagon 265Design Strategy and Assays 2671st Design: Exploring Substitution of Residues Susceptible for Isomerization, Cleavage, and Oxidation 2682nd Design: Exploring Substitution of Potential Deamidation Sites and Disruption of an Aggregation Prone Hydrophobic Region 2683rd Design: Combining the Learnings from Previous SAR Rounds 2704th Design 2725th Design 274Characterization of Dasiglucagon 279Physical and Chemical Stability of Dasiglucagon 279Rotation Study – Simulating Real Use by Patients 279Structural Characterization by Circular Dichroism 280Pharmacological Effect of Dasiglucagon in Humans 281Conclusion 282Amino Acid Abbreviations 283References 284Index 287