Foye's Principles of Medicinal Chemistry

Foye's Principles of Medicinal Chemistry

(Parte 1 de 11)

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Principles of



Principles of

Medicinal Chemistry SEVENTH EDITION

Edited By

Professor Emeritus

College of Pharmacy

University of Houston Houston, Texas

Professor Emeritus of Chemistry

Massachusetts College of Pharmacy and Health Sciences

Boston, Massachusetts

Associate Editors

Professor of Pharmacy Sciences

School of Pharmacy and Health Professions

Creighton University Omaha, Nebraska

Professor Pharmaceutical Sciences

College of Pharmacy and Allied Health Professions

St. John’s University Jamaica, New York

Acquisitions Editor : David Troy Product Managers : Andrea M. Klingler and Paula C. Williams Marketing Manager : Joy Fischer-Williams Designer : Doug Smock Compositor : SPi Global

Seventh Edition

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Library of Congress Cataloging-in-Publication Data Foye’s principles of medicinal chemistry / edited by Thomas L. Lemke, David A. Williams ; associate editors, Victoria F. Roche, S. William Zito. — 7th ed. p. ; cm.

Principles of medicinal chemistry Includes bibliographical references and indexes. ISBN 978-1-60913-345-0 I. Foye, William O. I. Lemke, Thomas L. II. Williams, David A., 1938- IV. Title: Principles of medicinal chemistry.

[DNLM: 1. Chemistry, Pharmaceutical. QV 744] 616.07’56—dc23 2011036313

DISCLAIMER Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations.

The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in this publication have Food and Drug Administration

(FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice.

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This textbook is dedicated to our students and to our academic colleagues who mentor these students in the principles and applications of medicinal chemistry. The challenge for the student is to master the chemical, pharmacological, pharmaceutical and therapeutic aspects of the drug and utilize the knowledge of medicinal chemistry to effectively communicate with prescribing clinicians, nurses and other members of the health care team, as well as in discussing drug therapy with patients.

Thomas L. Lemke David A. Williams Victoria F. Roche S. William Zito

As defi ned by IUPAC, medicinal chemistry is a chemistry-based discipline, involving aspects of the biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identifi cation and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships (SAR), which is the relationship between chemical structure and pharmacological activity for a series of compounds.

As we look back 38 years to the fi rst edition of Foye’s

Principles of Medicinal Chemistry and nearly 63 years to the fi rst edition of Wilson and Gisvold’s textbook, Organic Chemistry in Pharmacy (later renamed Textbook of Organic Medicinal and Pharmaceutical Chemistry), we can examine how the teaching of medicinal chemistry has evolved over the last half of the 20th century. Sixty years ago the approach to teaching drug classifi cation was based on chemical functional groups; in the 1970s it was the relationship between chemical structure and pharmacological activity for a series of compounds, and today medicinal chemistry involves the integration of these principles with pharmacology, pharmaceutics, and therapeutics into a single multi-semester course called pharmacodynamics, pharmacotherapeutics, or another similar name. Drug discovery and development will always maintain its role in traditional drug therapy, but its application to pharmacogenomics may well become the treatment modality of the future. In drug discovery, toxicogenomics is used to improve the safety of drugs mandated by U.S. Food and Drug administration by studying the adverse/toxic effects of drugs in order to draw conclusions on the toxic and safety risk to patients. The scope of knowledge in organic chemistry, biochemistry, pharmacology, and therapeutics allows students to make generalizations connecting the physicochemical properties of small organic molecules and peptides to the receptor and biochemical properties of living systems.

Creating new drugs to combat disease is a complex process. The shape of a drug must be right to allow it to bind to a specifi c disease-related protein (i.e., receptor) and to work effectively. This shape is determined by the core framework of the molecule and the relative orientation of functional groups in three dimensional space. As a consequence, these generalizations, validated by repetitive examples, emerge in time as principles of drug discovery and drug mechanisms, principles that describe the structural relationships between diverse organic molecules and the biomolecular functions that predict their mechanisms toward controlling diseases.

Medicinal chemistry is central to modern drug discovery and development. For most of the 20th century, the majority of drugs were discovered either by identifying the active ingredient in traditional natural remedies, by rational drug design, or by serendipity. As we have moved into the 21st century, drug discovery has focused on drug targets and high-throughput screening of drug hits and computer-assessed drug design to fi l its drug pipeline. Medicinal chemistry has advanced during the past several decades from not only synthesizing new compounds but to understanding the molecular basis of a disease and its control, identifying biomolecular targets implicated as disease-causing, and ultimately inventing specifi c compounds (called “hits”) that block the biomolecules from progressing to an illness or stop the disease in its tracks. Medicinal chemists use structure-activity relationships to improve the “hits” into “lead candidates” by optimizing their selectivity against the specifi c target, reducing drug activity against non-targets, and ensuring appropriate pharmacokinetic properties involving drug distribution and clearance.

These are tough times for the drug industry, as companies are looking at diminishing pipelines of potential new drugs, growing competition from generic versions of their drugs and increasing pressure from regulatory agencies to ensure that products are both safe and more effective than existing drugs. With the completion of sequencing of the human genome there are now greater challenges facing the drug industry for applications of new technologies in discovery and development. The number of drug targets once considered to be less than 500, has doubled and is expected to increase tenfold. Diseases that were once thought to be caused by a single pathology are now known to have differing etiologies requiring highly specifi c medications. In order to maintain its pipeline of new drugs, the drug industry is integrating biopharmaceuticals, such as therapeutic antibodies (e.g., in the treatment of arthritis), along with small-molecule drugs. As the drug industry undergoes reform, drug companies are developing collaborations with academia for new sources of drug molecules.

The editors of this textbook are all medicinal chemists, and our approaches to editing this seventh edition of Foye’s Principles of Medicinal Chemistry are infl uenced by our respective academic backgrounds. We believe that our collaboration on this textbook represents a melding of our perspectives that will provide new dimensions of appreciation and understanding for all students. In

Preface viii PREFACE

The intent of this section is to pose a problem at the beginning of the chapter to stimulate the student’s thinking as he/she reads through the chapter and then bring the learning “full circle” with the clinician’s and chemist’s solution to the case/problem revealed once the entire chapter has been read.

■A case study: Each of the above chapters ends with a case study (see the “Introduction to Medicinal Chemistry Case Studies” section of this preface). As with previous editions of Foye’s Principles of Medicinal Chemistry these cases are meant help the student evaluate their comprehension of the therapeutically relevant chemistry presented in the chapter and apply their understanding in a standardized format to solving the posed problem. All cases presented in this text underwent review by a practicing pharmacist to ensure clinical accuracy and relevance to contemporary practice.

In addition, the reader will fi nd at the beginning of most chapters a list of drugs (presented by generic or chemical names) discussed in that chapter. Additionally, at the beginning of each chapter, one will fi nd a list of the commonly used abbreviations in the chapter.

Several new chapters appear in the seventh edition, including Chapter 5, Membrane Drug Transporters; Chapter 16, Anesthetics: General and Local Anesthetics; Chapter 19, CNS Stimulants and Drugs of Abuse; and Chapter 42, Obesity and Nutrition. Lastly, a second color has been added to this edition to help emphasize particular points in the chapters. In most fi gures where drug metabolism occurs the point of metabolism is highlighted in red with coloration of the functionality which has been changed.

Student Resources

A Student Resource Center at Lemke7e includes the following materials:

■Full Text Online ■Additional Case Studies

■Answers to Additional Case Studies

■Practice Quiz Questions

■Drug Updates

■U.S. Drug Regulation: An Overview

Instructor Resources

We understand the demand on an instructor’s time. To facilitate and support your educational efforts, you will have access to Instructor Resources upon adoption of Foye’s Principles of Medicinal Chemistry, 7th edition. An Instructor’s Resource Center at http://thePoint.lww. com/Lemke7e includes the following:

■Full Text Online ■Image Bank

■Answers to In-Text Case Studies

■ Angel/Blackboard/WebCT Course Cartridges

■U.S. Drug Regulation: An Overview addition we recognize the benefi ts of medicinal chemistry can only be valuable if the science can be translated into improving the quality of life of our patients. As a result it is essential that the student apply the chemistry of the drugs to their patients and we have attempted to bridge the gap between the science of drugs and the real life situations through the use of scenarios and case studies. Finally in editing this multi-authored book we have tried to promote a consistent style in the organization of the respective chapters.

The organizational approach taken in this textbook builds from the principles of drug discovery, physicochemical properties of drug molecules, and ADMET (absorptiondistribution-metabolism-excretion-toxicity) to their integration into therapeutic substances with application to patient care. Our challenge has been to provide a comprehensive description of drug discovery and pharmacodynamic agents in an introductory textbook. To address the increasing emphasis in U.S. pharmacy schools on integrating medicinal chemistry with pharmacology and clinical pharmacy and the creation of one-semester principle courses, we organized the book into four parts: Part I: Principles of Drug Discovery; Part I: Drug Receptors Affecting Neurotransmission and Enzymes as Catalytic Receptors; Part I: Pharmacodynamic Agents (with further subdivision into drugs affecting different physiologic systems); and Part IV: Disease State Management. Parts I and I are designed for a course focused on principles of drug discovery and Parts I through IV are relevant to integrated courses in medicinal chemistry/pharmacodynamics/pharmacotherapeutics.

(Parte 1 de 11)