Drug discovery strategies for next-generation anti-diabetic and anti-obesity therapies

Diabetes ranks as the seventh leading cause of death globally, claiming 1.5 million victims annually, yet the complexity of energy metabolism makes pharmaceutical intervention difficult-often requiring simultaneous modulation of multiple drug targets. Trends in Drug Discovery in Diabetes and Obesity assembles drug developers from pharma companies who share hard-to-find insight on strategies for developing more efficient therapies.

The book surveys critical drug classes including GLP-1 receptor agonists, GIP antagonists, poly-agonist drugs, and long-acting insulin variants, covering both peptide and small molecule approaches. Selected case studies detail the discovery pathways of recently approved drugs, providing direct insight into the decision-making and optimization processes that led from target identification through clinical validation to market approval.

Readers will also find:

• Reviews of recent therapy developments and emerging treatment paradigms reshaping the current diabetes and obesity pharmacological landscape
• Evaluation of poly-agonist drug potential and their projected role in future multi-target therapeutic strategies for metabolic disorders
• Perspectives from industry professionals across pharmaceutical companies offering practical context rarely available in academic literature alone
• Coverage of peptide drug design strategies alongside small molecule approaches for addressing complex metabolic pathway modulation challenges
• Case studies tracing recently approved drugs from early discovery through optimization, illustrating real-world drug development decision frameworks

Designed for medicinal chemists, pharmaceutical chemists, and endocrinologists working in drug discovery and development, this volume delivers the strategic and mechanistic insight needed to advance the next generation of therapeutics targeting diabetes and obesity across both industry and academic research settings.

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, Lærke 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 VT