Contemporary Accounts in Drug Discovery and Development

CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT

A useful guide for medicinal chemists and pharmaceutical scientists

Drug discovery is a lengthy and complex process that typically involves identifying an unmet medical need, determining a biological target, chemical library screening to identify a lead, chemical optimization, preclinical studies and clinical trials. This process often takes many years to complete, and relies on practitioners' knowledge of chemistry and biology, but also--and perhaps more importantly--on experience. Improving the success rate in discovery and development through a thorough knowledge of drug discovery principles and advances in technology is critical for advancement in the field.

Contemporary Accounts in Drug Discovery and Development provides drug discovery scientists with the knowledge they need to quickly gain mastery of the drug discovery process. A thorough accounting is given for each drug covered within the book, as the authors provide pharmacology, drug metabolism, biology, drug development, and clinical studies for every case, with modern drug discovery principles and technologies incorporated throughout.

Contemporary Accounts in Drug Discovery and Development readers will also find

• Case histories used as an engaging way of learning about the drug discovery/development process

• Detailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studies

• The full history of individual marketed small molecule drugs

• Coverage of drug candidates that have passed Phase I clinical trials with different modalities, such as antibody drug conjugates (ADC), proteolysis-targeting chimera (PROTAC), and peptide drugs

• The application of new technologies in drug discovery such as DNA-encoded libraries (DEL), positron emission tomography (PET), and physics-based computational modeling employing free energy perturbation (FEP)

Contemporary Accounts in Drug Discovery and Development is a helpful tool for medicinal chemists, organic chemists, pharmacologists, and other scientists in drug research and process development. It may be considered essential reading for graduate courses in drug discovery, medicinal chemistry, drug synthesis, pharmaceutical science, and pharmacology. It is also a useful resource for pharmaceutical industry labs, as well as for libraries.

Auteur

Xianhai Huang, PhD, Executive Director and Head of Discovery Chemistry at InventisBio Co., Ltd.

Robert G. Aslanian, PhD, Associate Professor of Chemistry and Chair of the Department at New Jersey City University.

Wayne H. Tang, PhD, Executive Director and co-Head of Medicinal Chemistry at Schrödinger Inc.

Résumé
CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT A useful guide for medicinal chemists and pharmaceutical scientists Drug discovery is a lengthy and complex process that typically involves identifying an unmet medical need, determining a biological target, chemical library screening to identify a lead, chemical optimization, preclinical studies and clinical trials. This process often takes many years to complete, and relies on practitioners' knowledge of chemistry and biology, but alsoand perhaps more importantlyon experience. Improving the success rate in discovery and development through a thorough knowledge of drug discovery principles and advances in technology is critical for advancement in the field. Contemporary Accounts in Drug Discovery and Development provides drug discovery scientists with the knowledge they need to quickly gain mastery of the drug discovery process. A thorough accounting is given for each drug covered within the book, as the authors provide pharmacology, drug metabolism, biology, drug development, and clinical studies for every case, with modern drug discovery principles and technologies incorporated throughout. Contemporary Accounts in Drug Discovery and Development readers will also find

• Case histories used as an engaging way of learning about the drug discovery/development process
• Detailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studies
• The full history of individual marketed small molecule drugs
• Coverage of drug candidates that have passed Phase I clinical trials with different modalities, such as antibody drug conjugates (ADC), proteolysis-targeting chimera (PROTAC), and peptide drugs
• The application of new technologies in drug discovery such as DNA-encoded libraries (DEL), positron emission tomography (PET), and physics-based computational modeling employing free energy perturbation (FEP) Contemporary Accounts in Drug Discovery and Development is a helpful tool for medicinal chemists, organic chemists, pharmacologists, and other scientists in drug research and process development. It may be considered essential reading for graduate courses in drug discovery, medicinal chemistry, drug synthesis, pharmaceutical science, and pharmacology. It is also a useful resource for pharmaceutical industry labs, as well as for libraries.

Contenu
PREFACE

CONTRIBUTORS

CHAPTER 1 CURRENT DRUG DISCOVERY: GREAT CHALLENGES AND GREAT OPPORTUNITY (AN INTRODUCTION TO CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT)
*Jeffrey J. Hale*

CHAPTER 2 ADVANCED COMPUTATIONAL MODELING ACCELERATING SMALL-MOLECULE DRUG DISCOVERY: A GROWING TRACK RECORD OF SUCCESS
*Robert Abel*

2.1 Introduction

2.2 Essential Techniques

2.2.1 Target Validation and Feasibility Assessment

2.2.2 Hit Discovery

2.2.3 Hit-to-lead and Lead Optimization

2.3 Illustrative Applications

2.3.1 Modeling Support of Target Validation, Feasibility Assessment, and Hit Discovery for Acetyl-CoA Carboxylase (ACC)

2.3.2 Optimizing Selectivity in Lead Optimization for Tyrosine Kinase 2

2.3.3 Discovery of Novel Allosteric Covalent Inhibitors of KRASG12C

2.3.4 Supporting Hit to Lead Exploration for a Series of Phosphodiesterase 2A (PDE2A) Inhibitors

2.4 Conclusion and Future Outlook

References

CHAPTER 3 DISCOVERY AND DEVELOPMENT OF THE SOLUBLE GUANYLATE CYCLASE (sGC) STIMULATOR VERICIGUAT FOR THE TREATMENT OF CHRONIC HEART FAILURE
*Markus Follmann, Corina Becker, Lothar Roessig, Peter Sandner, and Johannes-Peter Stasch*

3.1 Introduction

3.2 sGC Stimulators as Treatment Option for Heart Failure

3.2.1 Persistent High Medical Need in High-risk Patients with Chronic HF

3.3 Medicinal Chemistry Program

3.4 Synthesis Routes towards Vericiguat

3.4.1 Medicinal Chemistry Route to Vericiguat

3.4.2 Development Chemistry Route to Vericiguat

3.5 Preclinical Studies

3.5.1 In Vitro Effects on Recombinant sGC and sGC Overexpressing Cells

3.5.2 Ex Vivo Effects on Isolated Blood Vessels and Hearts

3.5.3 In Vivo Effects in a Disease Model with Cardiovascular Disease and Heart- and Kidney Failure

3.6 Clinical Studies

3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers

3.6.2 Clinical Pharmacokinetics

3.6.3 Pharmacodynamic Interactions

3.7 Summary

References

CHAPTER 4 FINDING CURES FOR ALZHEMIER'S DISEASE: FROM GAMMA SECRETASE INHIBITORS TO GAMMA SECRETASE MODULATORS AND BETA SECRETASE INHIBITORS
*Xianhai Huang, Robert Aslanian*

4.1 Introduction

4.1.1 Alzheimer's Disease

4.1.2 Alzheimer's Disease and Amyloid Beta Theory

4.2 Gamma Secretase Inhibitors Drug Discovery and Development

4.2.1 Gamma Secretase Inhibitors Rationale

4.2.2 The Discovery of Gamma Secretase Inhibitors SCH 900229

4.2.2.1 The Discovery of 2,6-Disubstituted Piperidine Sulfonamide Gamma Secretase Inhibitors

4.2.2.2 The Discovery of Tricyclic Sulfones GSIs and a Preclinical Candidate SCH 900229

4.2.3 Gamma Secretase Inhibitors Summary

4.3 Gamma Secretase Modulator Drug Discovery and…