The Search for Anti-Inflammatory Drugs: Case Histories from Concept to Clinic / Edition 1

by Vincent J. Merluzzi, Julian Adams

Overview

Perspectives on Anti-Inflammatory Drugs Inflammation is a very complicated process of interrelated events and cas­ cades that does not allow for an easily defined, focused attack for drug discovery. It is evident from years of research and development that certain classes of compounds (e.g., NSAIDs, steroids, and so on) have had a meas­ ure of success in alleviating pain and even dampening cellularlhormonal mechanisms involved in the process. Clear, mechanism-related therapies (e.g., for arthritis) and targeted drugs (e.g., for transplantation) have not been available in the past and, in reality, research in inflammation has re­ lied on more phenomenological approaches for resolving symptoms or on blatant cytoreductive approaches in cases like organ transplantation. In the last decade, approaches that have revealed novel cellular pathways in which intervention is possible for lymphocyte regulation (for example, cyclosporine and FK506) and small molecular weight mediators (e.g., leu­ kotriene inhibitors) are now either standard therapy or will be in a short time. These latter approaches have been the result of research from the 1970s up to the present.

Product Details

ISBN-13:	9781461598480
Publisher:	Birkhäuser Boston
Publication date:	02/05/2012
Edition description:	Softcover reprint of the original 1st ed. 1995
Pages:	304
Product dimensions:	6.10(w) x 9.25(h) x 0.03(d)

About the Author

Merluzzi, Vincent J. (Boehringer Ingelheim Pharmaceuticals, Inc.); Adams, Julian (MyoGenics, Inc.)

The contributors represent the specialties of medicinal chemistry, pharmacology, immunology and infectious diseases, and inflammatory diseases. Most are from pharmaceutical companies in the U.S., Canada, Japan, and Switzerland. Institutions prominently represented include Abbott Labs, Zeneca Pharmaceuticals, Sandoz Pharmaceuticals, Ltd., Fujisawa Pharmaceutical Co., and Pfizer.

Table of Contents

1 The Discovery of Drugs to Treat Arthritis: A Historical View.- 2 The History of the Discovery and Development of Cyclosporine (Sandimmune®).- 3 Discovery and Development of FK506 (Tacrolimus), A Potent Immunosuppressant of Microbial Origin.- 4 Discovery of Sulindac, a Reversible Prodrug, as a Second-Generation Indomethacin.- 5 The Discovery of Zileuton (Leutrol®).- 6 Discovery of Accolate™ (ICI 204,219), a Peptide Leukotriene Antagonist for Asthma.- 7 Discovery of ZD2138, a Potent, Selective, Well-Tolerated, Nonredox Inhibitor of the Enzyme 5-Lipoxygenase.- 8 Development of MK 0591: An Orally Active Leukotriene Biosynthesis Inhibitor with a Novel Mechanism of Action.- 9 Discovery of BIRM 270: A New Class of Leukotriene Biosynthesis Inhibitors.- 10 Discovery and Development of the Immunomodulatory Azaspiranes.- Keyword Index.

Editorial Reviews

3 Stars from Doody

This book is a collection of nine chapters describing successful drug discovery efforts. As Otterness, at the end of the first chapter, observes: ...Drugs are now targeted extremely specifically against a single mechanism. This greatly reduces the chances of undesired effects. Today the challenge for drug discovery is rarely whether we can develop an inhibitor of a specific mechanism....Can we choose a target mechanism well enough that an inhibitor will have a good probability of being therapeutically effective?... This book may be instructive to those beginning careers in pharmaceutical science and help those already in the trenches recover a view of the larger picture. Based on the histories presented here, all drug candidates meet determined resistance somewhere along their path to approval, and each requires one or more champions to shepherd them through. An introductory historical perspective nicely sets the stage for the chapters that follow. Each chapter serves as an example of one of three approaches to drug discovery. Chapters 2 and 3 demonstrate the utility of screening rnicrobiological extracts for drug candidates or lead molecules. Chapters 4 and 10 describe medicinal chemistry approaches, beginning with known drugs, that seek to improve efficacy, bioavailability, and/or reduce side effects. The remaining chapters describe mechanistic approaches, targeting a receptor or enzyme with lead compounds based on substrates, or discovered from compound library screens. The individual contributions are well written and interesting, providing a sense of the team effort required for success. However, the chapter on cyclosporine is too long and somewhat self-aggrandizing. Readers notintimately involved with the industry may get bogged down in details of the medicinal chemistry and clinical trials in some chapters, and expanded discussion of the decision-making processes would have been welcomed. Still, a careful reader of this book will come away with the message that good science is not enough for successful drug discovery. In addition to a well-coordinated team effort on the part of dedicated chemists and biologists, success depends on persistence, good decision-making processes, and pure luck.

Brian K. Brandley

Contributes to the history of modern pharmacology by presenting in both a narrative and technical format the actual nature of the discovery or development process for ten anti-inflammatory drugs. Demonstrates to non-specialists and graduate students how concepts are started and how the success or failure of the project emerges from intricate thinking, nuances, prejudices, and scientific and political processes. A companion volume on antiviral drugs is planned. Annotation c. Book News, Inc., Portland, OR (booknews.com)

Booknews

Reviewer: Brian K. Brandley, PhD (Rush Medical College of Rush University)
Description: This book is a collection of nine chapters describing successful drug discovery efforts.
Purpose: As Otterness, at the end of the first chapter, observes: "...Drugs are now targeted extremely specifically against a single mechanism. This greatly reduces the chances of undesired effects. Today the challenge for drug discovery is rarely whether we can develop an inhibitor of a specific mechanism....Can we choose a target mechanism well enough that an inhibitor will have a good probability of being therapeutically effective?..."
Audience: This book may be instructive to those beginning careers in pharmaceutical science and help those already in the trenches recover a view of the larger picture. Based on the histories presented here, all drug candidates meet determined resistance somewhere along their path to approval, and each requires one or more champions to shepherd them through.
Features: An introductory historical perspective nicely sets the stage for the chapters that follow. Each chapter serves as an example of one of three approaches to drug discovery. Chapters 2 and 3 demonstrate the utility of screening rnicrobiological extracts for drug candidates or lead molecules. Chapters 4 and 10 describe medicinal chemistry approaches, beginning with known drugs, that seek to improve efficacy, bioavailability, and/or reduce side effects. The remaining chapters describe mechanistic approaches, targeting a receptor or enzyme with lead compounds based on substrates, or discovered from compound library screens.
Assessment: The individual contributions are well written and interesting, providing a sense of the team effort required for success. However, the chapter on cyclosporine is too long and somewhat self-aggrandizing. Readers not intimately involved with the industry may get bogged down in details of the medicinal chemistry and clinical trials in some chapters, and expanded discussion of the decision-making processes would have been welcomed. Still, a careful reader of this book will come away with the message that good science is not enough for successful drug discovery. In addition to a well-coordinated team effort on the part of dedicated chemists and biologists, success depends on persistence, good decision-making processes, and pure luck.

Doody's Review Service