Foye's Principles of Medicinal Chemistry PDF 7th Edition

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 ‫ﮐﺎدوﺳﻪ ﻣﺮﺟﻊ ﮐﺘﺎﺑﻬﺎی اﻟﮑﱰوﻧﯿﮏ ﻻﺗﯿﻦ ﭘﺰﺷﮑﯽ‬ ‫ﮐﺎدوﺳﻪ ﻣﺮﺟﻊ ﻓﯿﻠﻢ و ﻧﺮماﻓﺰارﻫﺎی آﻣﻮزﺷﯽ ﭘﺰﺷﮑﯽ‬ ‫ﮐﺎدوﺳﻪ ﺳﺎﯾﺖ ﺟﺎﻣﻊ اﻃﻼﻋﺎت ﭘﺰﺷﮑﯽ‬ ‫‪WWW.KADUSE.COM‬‬  ‫دﯾﮕﺮ ﮐﺘﺐ ﺑﯿﻮﺷﯿﻤﯽ‬ Title Autour(s) Year Marks' Basic Medical Biochemistry Alisa Peet/ Michael A. Lieberman 2013 Fundamentals of Biochemistry: Life at the Molecular Level Donald Voet / Judith G. Voet 2013 Absolute Ultimate Guide for Lehninger Principles of Biochemistry David L. Nelson / Michael M. Cox 2013 Lehninger Principles of Biochemistry David L. Nelson / Michael M. Cox 2013 Harpers Illustrated Biochemistry 29th Edition Robert Murray / David Bender 2012 Clinical Biochemistry and Metabolic Medicine Martin A Crook 2012 Elsevier's Integrated Review Biochemistry John W. Pelley 2012 Principles of Medical Biochemistry Gerhard Meisenberg / William H. Simmons 2012 Clinical Chemistry William J. Marshall / Stephen K Bangert 2012 Protein Microarrays: Methods and Protocols Ulrike Korf 2011 Principles of Biochemistry Laurence A. Moran/ Robert A Horton 2011 Biochemistry-Berg Jeremy M. Berg John /L. Tymoczko Lubert Stryer 2011 Dyneins: Structure, Biology and Disease Stephen M. King 2011 Textbook of Biochemistry with Clinical Correlations Thomas M. Devlin 2011 Rapid Review Biochemistry John W. Pelley / Edward F. Goljan 2011 BRS Biochemistry, Molecular Biology, and Genetics Todd A. Swanson / Sandra I. Kim 2010 Lippincott's Illustrated Q&A Review of Biochemistry Michael A. Lieberman / Rick Ricer 2010 Clinical Chemistry: Techniques, Principles, Correlations -Bishop Michael L. Bishop / Edward P. Fody 2010 Tietz Fundamentals of Clinical Chemistry Carl A. Burtis / David E. Bruns 2008 ١  FOYE’S Principles of Medicinal Chemistry SEVENTH EDITION Lemke_FM.indd i 12/17/2011 3:35:06 PM Lemke_FM.indd ii 12/17/2011 3:35:07 PM  FOYE’S Principles of Medicinal Chemistry SEVENTH EDITION Edited By Associate Editors THOMAS L. LEMKE, PHD VICTORIA F. ROCHE, PHD Professor Emeritus Professor of Pharmacy Sciences College of Pharmacy School of Pharmacy and Health Professions University of Houston Creighton University Houston, Texas Omaha, Nebraska DAVID A. WILLIAMS, PHD S. WILLIAM ZITO, PHD Professor Emeritus of Chemistry Professor Pharmaceutical Sciences Massachusetts College of Pharmacy and College of Pharmacy and Allied Health Health Sciences Professions Boston, Massachusetts St. John’s University Jamaica, New York Lemke_FM.indd iii 12/17/2011 3:35:07 PM  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 Copyright © 2013 Lippincott Williams & Wilkins, a Wolters Kluwer business 351 West Camden Street Two Commerce Square Baltimore, MD 21201 2001 Market Street Philadelphia, PA 19103 Printed in China All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appear- ing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via website at lww.com (products and services). 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. II. Lemke, Thomas L. III. 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 omis- sions 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 respon- sibility 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. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: http://www.lww.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST. 9 8 7 6 5 4 3 2 1 Lemke_FM.indd iv 12/17/2011 3:35:08 PM  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 Kaduse.com Lemke_FM.indd v 12/17/2011 3:35:08 PM  Kaduse.com Lemke_FM.indd vi 12/17/2011 3:35:08 PM  Preface As defined by IUPAC, medicinal chemistry is a chemistry-based Medicinal chemistry is central to modern drug discov- discipline, involving aspects of the biological, medical and phar- ery and development. For most of the 20th century, the maceutical sciences. It is concerned with the invention, discov- majority of drugs were discovered either by identifying ery, design, identification and preparation of biologically active the active ingredient in traditional natural remedies, by compounds, the study of their metabolism, the interpretation of rational drug design, or by serendipity. As we have moved their mode of action at the molecular level and the construction into the 21st century, drug discovery has focused on drug of structure-activity relationships (SAR), which is the relation- targets and high-throughput screening of drug hits and ship between chemical structure and pharmacological activity for computer-assessed drug design to fill its drug pipeline. a series of compounds. Medicinal chemistry has advanced during the past sev- As we look back 38 years to the first edition of Foye’s eral decades from not only synthesizing new compounds Principles of Medicinal Chemistry and nearly 63 years to the first but to understanding the molecular basis of a disease and edition of Wilson and Gisvold’s textbook, Organic Chemistry its control, identifying biomolecular targets implicated as in Pharmacy (later renamed Textbook of Organic Medicinal disease-causing, and ultimately inventing specific com- and Pharmaceutical Chemistry), we can examine how the pounds (called “hits”) that block the biomolecules from teaching of medicinal chemistry has evolved over the last progressing to an illness or stop the disease in its tracks. half of the 20th century. Sixty years ago the approach to Medicinal chemists use structure-activity relationships to teaching drug classification was based on chemical func- improve the “hits” into “lead candidates” by optimizing tional groups; in the 1970s it was the relationship between their selectivity against the specific target, reducing drug chemical structure and pharmacological activity for a series activity against non-targets, and ensuring appropriate of compounds, and today medicinal chemistry involves the pharmacokinetic properties involving drug distribution integration of these principles with pharmacology, phar- and clearance. maceutics, and therapeutics into a single multi-semester These are tough times for the drug industry, as com- course called pharmacodynamics, pharmacotherapeutics, panies are looking at diminishing pipelines of potential or another similar name. Drug discovery and development new drugs, growing competition from generic versions will always maintain its role in traditional drug therapy, but of their drugs and increasing pressure from regula- its application to pharmacogenomics may well become the tory agencies to ensure that products are both safe and treatment modality of the future. In drug discovery, toxi- more effective than existing drugs. With the comple- cogenomics is used to improve the safety of drugs man- tion of sequencing of the human genome there are now dated by U.S. Food and Drug administration by studying greater challenges facing the drug industry for applica- the adverse/toxic effects of drugs in order to draw conclu- tions of new technologies in discovery and development. sions on the toxic and safety risk to patients. The scope of The number of drug targets once considered to be less knowledge in organic chemistry, biochemistry, pharmacol- than 500, has doubled and is expected to increase ten- ogy, and therapeutics allows students to make generaliza- fold. Diseases that were once thought to be caused by tions connecting the physicochemical properties of small a single pathology are now known to have differing eti- organic molecules and peptides to the receptor and bio- ologies requiring highly specific medications. In order chemical properties of living systems. to maintain its pipeline of new drugs, the drug industry Creating new drugs to combat disease is a complex is integrating biopharmaceuticals, such as therapeutic process. The shape of a drug must be right to allow it to antibodies (e.g., in the treatment of arthritis), along with bind to a specific disease-related protein (i.e., receptor) small-molecule drugs. As the drug industry undergoes and to work effectively. This shape is determined by the reform, drug companies are developing collaborations core framework of the molecule and the relative orien- with academia for new sources of drug molecules. tation of functional groups in three dimensional space. The editors of this textbook are all medicinal chem- As a consequence, these generalizations, validated by ists, and our approaches to editing this seventh edition repetitive examples, emerge in time as principles of drug of Foye’s Principles of Medicinal Chemistry are influenced by discovery and drug mechanisms, principles that describe our respective academic backgrounds. We believe that the structural relationships between diverse organic mol- our collaboration on this textbook represents a meld- ecules and the biomolecular functions that predict their ing of our perspectives that will provide new dimensions mechanisms toward controlling diseases. Kaduse.com of appreciation and understanding for all students. In vii Lemke_FM.indd vii 12/17/2011 3:35:08 PM  viii PREFACE addition we recognize the benefits of medicinal chemis- The intent of this section is to pose a problem at the try can only be valuable if the science can be translated beginning of the chapter to stimulate the student’s into improving the quality of life of our patients. As a thinking as he/she reads through the chapter and result it is essential that the student apply the chemistry then bring the learning “full circle” with the clini- of the drugs to their patients and we have attempted to cian’s and chemist’s solution to the case/problem bridge the gap between the science of drugs and the real revealed once the entire chapter has been read. life situations through the use of scenarios and case stud- A case study: Each of the above chapters ends with ies. Finally in editing this multi-authored book we have a case study (see the “Introduction to Medicinal tried to promote a consistent style in the organization of Chemistry Case Studies” section of this preface). the respective chapters. As with previous editions of Foye’s Principles of Medicinal Chemistry these cases are meant help ORGANIZATIONAL PHILOSOPHY the student evaluate their comprehension of the therapeutically relevant chemistry presented in the The organizational approach taken in this textbook builds chapter and apply their understanding in a stan- from the principles of drug discovery, physicochemical dardized format to solving the posed problem. All properties of drug molecules, and ADMET (absorption- cases presented in this text underwent review by a distribution-metabolism-excretion-toxicity) to their inte- practicing pharmacist to ensure clinical accuracy gration into therapeutic substances with application to and relevance to contemporary practice. patient care. Our challenge has been to provide a com- prehensive description of drug discovery and pharmaco- In addition, the reader will find at the beginning of most dynamic agents in an introductory textbook. To address chapters a list of drugs (presented by generic or chemi- the increasing emphasis in U.S. pharmacy schools on cal names) discussed in that chapter. Additionally, at the integrating medicinal chemistry with pharmacology beginning of each chapter, one will find a list of the com- and clinical pharmacy and the creation of one-semester monly used abbreviations in the chapter. principle courses, we organized the book into four parts: Several new chapters appear in the seventh edition, includ- Part I: Principles of Drug Discovery; Part II: Drug ing Chapter 5, Membrane Drug Transporters; Chapter Receptors Affecting Neurotransmission and Enzymes as 16, Anesthetics: General and Local Anesthetics; Chapter Catalytic Receptors; Part III: Pharmacodynamic Agents 19, CNS Stimulants and Drugs of Abuse; and Chapter 42, (with further subdivision into drugs affecting differ- Obesity and Nutrition. Lastly, a second color has been added ent physiologic systems); and Part IV: Disease State to this edition to help emphasize particular points in the Management. Parts I and II are designed for a course chapters. In most figures where drug metabolism occurs the focused on principles of drug discovery and Parts II point of metabolism is highlighted in red with coloration of through IV are relevant to integrated courses in medicinal the functionality which has been changed. chemistry/pharmacodynamics/pharmacotherapeutics. STUDENT AND INSTRUCTOR RESOURCES WHAT IS NEW IN THIS EDITION Student Resources The pharmacist sits at the interface between the health- A Student Resource Center at http://thePoint.lww.com/ care system and the patient. The pharmacist has the Lemke7e includes the following materials: responsibility for improving the quality of life of the patient by assuring the appropriate use of pharmaceuti- Full Text Online cals. To do this appropriately, the pharmacist must bring Additional Case Studies together the basic sciences of chemistry, biology, biophar- Answers to Additional Case Studies maceutics and pharmacology with the clinical sciences. Practice Quiz Questions In an attempt to relate the importance of medicinal Drug Updates chemistry to the clinical sciences, each of the chapters U.S. Drug Regulation: An Overview in Part II, Pharmacodynamic Agents, through Part IV, Disease State Management, includes the following: Instructor Resources We understand the demand on an instructor’s time. A clinical significance section: At the beginning of To facilitate and support your educational efforts, you most chapters, a practicing clinician has provided a will have access to Instructor Resources upon adoption statement of the clinical significance of medicinal of Foye’s Principles of Medicinal Chemistry, 7th edition. An chemistry to the particular therapeutic class of drugs. Instructor’s Resource Center at http://thePoint.lww. A clinical scenario section: At the beginning of the com/Lemke7e includes the following: chapters in Part III and IV the clinician has pro- vided a brief clinical scenario (mini-case) or real- Full Text Online life therapeutic problem related to the disease state Image Bank under consideration. A solution to the case or prob- Answers to In-Text Case Studies lem appears at the end of the chapter along with the medicinal chemist’s analysis of the solution. Kaduse.com Angel/Blackboard/WebCT Course Cartridges U.S. Drug Regulation: An Overview Lemke_FM.indd viii 12/17/2011 3:35:08 PM  PREFACE ix ACKNOWLEDGEMENTS professional recommendation, students must conduct a thorough analysis of key structure activity relationships We are indebted to our talented and conscientious con- (SAR) in order to predict such things as relative potency, tributors, for without them this book would not exist. receptor selectivity, duration of action and potential for This includes chapter authors, clinicians who wrote both adverse reactions, and then apply the knowledge gained the clinical significance sections and scenarios, and to to meet the patient’s therapeutic needs. Victoria Roche and Sandy Zito for creation of the excit- The therapeutic choices we offer in each case have ing and educational case studies. We also thank our been purposefully selected to allow students to review the respective academic institutions for the use of institu- therapeutically relevant chemistry of different classes of tional resources and for the freedom to exercise the cre- drugs used to treat a particular disease. We recognize that ative juices needed to bring new ideas to a textbook in this approach might occasionally omit some compounds medicinal chemistry. viewed by practitioners as drugs of choice within a class We are grateful for the many people at Lippincott or the formulary entry at their practice sites. Faculty Williams & Wilkins who were there to answer questions, employing the cases as in-class or take-home assignments make corrections, and support us through their encour- might alter the structural choices provided to meet their aging words. Many of those who shepherded this book teaching and learning goals, and this is certainly accept- through the complex process of publication worked able. Regardless of how they are used, students working behind the scene and are not known to us, but we specifi- thoughtfully and scientifically through the cases will not cally acknowledge Andrea M. Klingler and Paula Williams only master chemical concepts and principles and rein- (Product Managers), and David Troy (Acquisitions force basic SAR, but also learn how to actively use their Editor) for their kind and gentle prodding. unique knowledge of drug chemistry when thinking Finally, we want to acknowledge our respective critically about patient care. This skill will be invaluable spouses, Pat and Gail, who were supportive of this time- when, as practitioners, they are faced with a full gamut of consuming labor of love. Untold hours were spent away therapeutic options to analyze in order to ensure the best from the family sitting in front of our computers in order therapeutic outcomes for their patients. to bring this project to fruition. In short, here’s what we hope students will gain by Thomas L. Lemke, PhD working our cases. David A. Williams, PhD Mastery of the important concepts needed to be successful in the medicinal chemistry component INTRODUCTION TO MEDICINAL CHEMISTRY of the pharmacy curriculum; CASE STUDIES An ability to identify the relevance of drug chem- istry to pharmacological action and therapeutic We are pleased to share our newest medicinal chemis- utility, and to discriminate between therapeutic try case studies with student and faculty users of Foye’s options based on that understanding; Principles of Medicinal Chemistry. One case study is pro- An enhanced ability to think critically and scientifi- vided at the end of most chapters. This preface is written cally about drug use; to explain their scope and purpose, and to help those A commitment to caring about the impact of pro- who are unfamiliar with our technique of illustrating the fessional decisions on patients’ quality of life; therapeutic relevance of chemistry get the most out of The ability to demonstrate the unique role of the the exercise. pharmacist as the chemist of the health care team. Like the more familiar therapeutic case studies, medicinal chemistry case studies are clinical scenarios We hope you find these case studies both challenging that present a patient in need of a pharmacist’s expert and enjoyable, and we encourage you to use them as a intervention. The learner, most commonly in the role of springboard to more in-depth discussions with your fac- the pharmacist, evaluates the patient’s clinical and per- ulty and/or colleagues about the role of chemistry in sonal situation and makes a drug product selection from rational therapeutic decision-making. a limited number of therapeutic choices. However, in a medicinal chemistry case study, only the structures of the Victoria F. Roche, PhD potential therapeutic candidates are given. To make their S. William Zito, PhD Kaduse.com Lemke_FM.indd ix 12/17/2011 3:35:08 PM  Kaduse.com Lemke_FM.indd x 12/17/2011 3:35:09 PM  Contributors Ali R. Banijamali, PhD Marc Gillespie, PhD Ironwood Pharmaceuticals St. John’s University Cambridge, MA College of Pharmacy and Allied Health Professions Queens, NY Raymond G. Booth, PhD University of Florida Richard A. Glennon, PhD College of Pharmacy Virginia Commonwealth University Gainsville, FL School of Pharmacy Richmond, VA Ronald Borne, PhD The University of Mississippi Robert K. Griffith, PhD School of Pharmacy West Virginia University University, MS School of Pharmacy Morgantown, WV Robert W. Brueggemeier, PhD The Ohio State University Marc Harrold, PhD College of Pharmacy Duquesne University Columbus, OH Mylan School of Pharmacy Pittsburgh, PA James T. Dalton, PhD The Ohio State University Peter J. Harvison, PhD College of Pharmacy University of the Sciences in Philadelphia Columbus, OH Philadelphia College of Pharmacy Philadelphia, PA Małgorzata Dukat, PhD Virginia Commonwealth University Sunil S. Jambhekar, PhD School of Pharmacy Lake Erie College of Osteopathic Medicine Richmond, VA Bradenton, FL E. Kim Fifer, PhD David A. Johnson, PhD University of Arkansas for Medical Sciences Duquesne University College of Pharmacy Mylan School of Pharmacy Little Rock, AR Pittsburgh, PA Elmer J. Gentry, PhD Stephen Kerr, PhD Chicago State University Massachusetts College of Pharmacy and Health College of Pharmacy School of Pharmacy Chicago, IL Boston, MA Kaduse.com xi Lemke_FM.indd xi 12/17/2011 3:35:09 PM  xii CONTRIBUTORS Douglas Kinghorn, PhD Marilyn Morris, PhD The Ohio State University University of Buffalo - SUNY College of Pharmacy School of Pharmacy and Pharmaceutical Sciences Columbus, OH Buffalo, NY James J. Knittel, PhD Bridget L. Morse Western New England College University of Buffalo - SUNY School of Pharmacy School of Pharmacy and Pharmaceutical Sciences Springfield, MA Buffalo, NY Vijaya L. Korlipara, PhD Wendel L. Nelson, PhD St. John’s University University of Washington College of Pharmacy and Allied Health Professions School of Pharmacy Queens, NY Seattle, WA Barbara LeDuc, PhD John L. Neumeyer, PhD Massachusetts College of Pharmacy and Health Harvard Medical School School of Pharmacy McLean Hospital Boston, MA Belmont, MA Thomas L. Lemke, PhD University of Houston Gary O. Rankin, PhD College of Pharmacy Marshall University Houston, TX School of Medicine Huntington, WV Mark Levi, PhD US Food & Drug Administration Edward B. Roche, PhD National Center for Toxicological Research University of Nebraska Division of Neurotoxicology College of Pharmacy Jefferson, AR Omaha, NE Matthias C. Lu, PhD Victoria F. Roche, PhD University of Illinois at Chicago Creighton University College of Pharmacy School of Pharmacy and Health Professions Chicago, IL Omaha, NE Timothy Maher, PhD David A. Williams, PhD Massachusetts College of Pharmacy and Health Massachusetts College of Pharmacy and Health Sciences Sciences School of Pharmacy School of Pharmacy Boston, MA Boston, MA Ahmed S. Mehanna, PhD Norman Wilson, BSc, PhD, CChem, FRSC Massachusetts College of Pharmacy and Health University of Edinburgh Sciences Edinburgh, Scotland School of Pharmacy Boston, MA Patrick M. Woster, PhD Medical University of South Carolina Duane D. Miller, PhD College of Pharmacy The University of Tennessee Charleston, SC College of Pharmacy Memphis, TN Tanaji T. Talele, PhD Nader H. Moniri St. John’s University Mercer University College of Pharmacy and Allied Health College of Pharmacy and Health Sciences Professions Atlanta, GA Queens, NY Kaduse.com Lemke_FM.indd xii 12/17/2011 3:35:09 PM  CONTRIBUTORS xiii Robin Zavod, PhD David Hayes, PharmD Midwestern University, Chicago University of Houston College of Pharmacy College of Pharmacy Chicago, IL Houston, TX S. William Zito, PhD Elizabeth B. Hirsch, PharmD, BCPS St. John’s University Northeastern University College of Pharmacy and Allied Health Professios School of Pharmacy Queens, NY Boston, MA Clinical Scenario and Clinical Jill T. Johnson, PharmD, BCPS Significance University of Arkansas for Medical Sciences College of Pharmacy Paul Arpino, RPh Little Rock, AR Harvard Medical School Department of Pharmacy Vijaya L. Korlipara, PhD Massachusetts General Hospital St. John’s University Boston, MA College of Pharmacy and Allied Health Professions Queens, NY Kim K. Birtcher, MS, PharmD, BCPS, CDE, CLS University of Houston Beverly Lukawski, PharmD College of Pharmacy Creighton University Houston, TX School of Pharmacy and Health Professions Omaha, NE Jennifer Campbell, PharmD Creighton University Timothy Maher, PhD School of Pharmacy and Health Professions Massachusetts College of Pharmacy and Health Omaha, NE Sciences School of Pharmacy Judy Cheng, PharmD Boston, MA Massachusetts College of Pharmacy and Health Sciences Susan W. Miller, PharmD School of Pharmacy Mercer University Boston, MA College of Pharmacy and Health Sciences Atlanta, GA Elizabeth Coyle, PharmD University of Houston Kathryn Neill, PharmD College of Pharmacy University of Arkansas for Medical Sciences Houston, TX College of Pharmacy Little Rock, AR Joseph V. Etzel, PharmD St. John’s University Kelly Nystrom, PharmD, BCOP College of Pharmacy and Allied Health Professions Creighton University Queens, NY School of Pharmacy and Health Professions Omaha, NE Marc Gillepspie, PhD St. John’s University Nancy Ordonez, PharmD College of Pharmacy and Allied Health Professions University of Houston Queens, NY College of Pharmacy Houston, TX Michael Gonyeau, PharmD, BCPS Northeastern University Anne Pace, PharmD School of Pharmacy University of Arkansas for Medical Sciences Boston, MA College of Pharmacy Little Rock, AR Kaduse.com Lemke_FM.indd xiii 12/17/2011 3:35:09 PM  xiv CONTRIBUTORS Nathan A. Painter, PharmD, CDE Autumn Stewart, PharmD University of California, San Diego Duquesne University Skaggs School of Pharmacy and Pharmaceutical Science School of Pharmacy La Jolla, CA Pittsburgh, PA Thomas L. Rihn, PharmD Tanaji T. Talele, PhD Duquesne University St. John’s University School of Pharmacy College of Pharmacy and Allied Health Professions Pittsburgh, PA Queens, NY Jeffrey T. Sherer, PharmD, MPH, BCPS, CGP Mark D. Watanabe, PharmD, PhD, BCPP University of Houston Northeastern University College of Pharmacy School of Pharmacy Houston, TX Boston, MA Douglas Slain, PharmD, BCPS West Virginia University College of Pharmacy Morgantown, WV Kaduse.com Lemke_FM.indd xiv 12/17/2011 3:35:09 PM  Reviewers Michael Adams, PharmD, PhD Kennerly Patrick, PhD Med Chem Assistant Professor Professor Pharmaceutical Sciences Pharmaceutical Sciences Campbell University School of Pharmacy Medical University of South Carolina Buies Creek, NC College of Pharmacy Charleston, SC Zhe-Sheng Chen, MD, PhD Associate Professor Tanaji Talele, PhD Pharmaceutical Science Associate Professor of Medicinal Chemistry St. John’s University Department of Pharmaceutical Sciences Queens, NY College of Pharmacy & Allied Health Professions St. John’s University John Cooperwood, PhD Queens, NY Associate Professor Pharmaceutical Sciences Ganeshsingh Thakur, PhD Florida Agricultural and Mechanical University College Center for Drug Discovery of Pharmacy Assistant Professor Tallahassee, FL Pharmaceutical Sciences Northeastern University Matthew J. DellaVecchia, PhD Boston, MA Assistant Professor of Pharmaceutical Sciences Gregory School of Pharmacy Constance Vance, PhD Palm Beach Atlantic University Adjunct Assistant Professor Palm Beach, FL University of North Carolina at Chapel Hill Chapel Hill, NC Marc Harrold, PhD Professor of Medicinal Chemistry Mylan School of Pharmacy Duquesne University Pittsburgh, PA Kaduse.com xv Lemke_FM.indd xv 12/17/2011 3:35:09 PM  Kaduse.com Lemke_FM.indd xvi 12/17/2011 3:35:10 PM  History and Evolution of Medicinal Chemistry J O H N L. N E U M E Y E R The unprecedented increase in human life expectancy, which has American Indians, and the ipecacuanha root containing almost doubled in a hundred years, is mainly due to drugs and to emetine was used in Brazil for the treatment of dysen- those who discovered them (1). tery and is still used for the treatment of amebiasis. The The history of all fields of science is comprised of the early explorers found that the South American Indians ideas, knowledge, and available tools that have advanced also chewed coca leaves (containing cocaine) and used contemporary knowledge. The spectacular advances in mushrooms (containing methylated tryptamine) as hal- medicinal chemistry over the years are no exception. lucinogens. In ancient Greek apothecary shops, herbs Alfred Burger (1) stated that “…the great advances of such as opium, squill, and Hyoscyamus, viper toxin, and medicinal chemistry have been achieved by two types of metallic drugs such as copper and zinc ores, iron sulfate, investigators: those with the genius of prophetic logic, and cadmium oxide could be found. who have opened a new field by interpreting correctly a few well-placed experiments, whether they pertained The Middle Ages to the design or the mechanism of action of drugs; and The basic studies of chemistry and physics shifted from those who have varied patiently the chemical structures the Greco-Roman to the Arabian alchemists between the of physiologically active compounds until a useful drug 13th and 16th centuries. Paracelsus (1493–1541) glori- could be evolved as a tool in medicine.” To place the fied antimony and its salts in elixirs as cure-alls in the development of medicinal chemical research into its belief that chemicals could cure disease. proper perspective, one needs to examine the evolution of the ideas and concepts that have led to our present The 19th Century: Age of Innovation and Chemistry knowledge. The 19th century saw a great expansion in the knowledge of chemistry, which greatly extended the herbal pharma- Drugs of Antiquity copeia that had previously been established. Building The oldest records of the use of therapeutic plants and on the work of Antoine Lavoisier, chemists throughout minerals are derived from the ancient civilizations of the Europe refined and extended the techniques of chemical Chinese, the Hindus, the Mayans of Central America, and analysis. The synthesis of acetic acid by Adolph Kolbe in the Mediterranean peoples of antiquity. The Emperor 1845 and of methane by Pierre Berthelot in 1856 set the Shen Nung (2735 bc) compiled what may be called a stage for organic chemistry. Pharmacognosy, the science pharmacopeia including ch’ang shang, an antimalarial that deals with medicinal products of plant, animal, or alkaloid, and ma huang, from which ephedrine was iso- mineral origin in their crude state, was replaced by physi- lated. Chaulmoogra fruit was known to the indigenous ologic chemistry. The emphasis was shifted from finding Kaduse.com 1 Lemke_Historical Perspective.indd 1 12/9/2011 12:31:01 AM  2 HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY new medicaments from the vast world of plants to finding military surgeon who first noticed distinctive psychotro- the active ingredients that accounted for their pharmaco- pic effects in man; or Pierre Deniker and Jean Delay, logic properties. The isolation of morphine by Friedrich French psychiatrists who clearly outlined what has now Sertürner in 1803, the isolation of emetine from ipeca- become its accepted use in psychiatry and without whose cuanha by Pierre-Joseph Pelletier in 1816, and his puri- endorsement and prestige Rhone-Poulenc might never fication of caffeine, quinine, and colchicine in 1820 all have developed it further as an antipsychotic? Because of contributed to the increased use of “pure” substances as the bitter disputes over the discovery of chlorpromazine, therapeutic agents. In the 19th century, digitalis was used no Nobel Prize was ever awarded for what has been the by the English physician and botanist, William Withering, single most important breakthrough in psychiatric treat- for the treatment of edema. Albert Niemann isolated ment (Fig. 1). cocaine in 1860, and in 1864, he isolated the active ingre- The discovery of the antidepressant effects of the anti- dient, physostigmine, from the Calabar bean. As a result tubercular drug iproniazid (isopropyl congener of isoni- of these discoveries and the progress made in organic azid), which has monoamine oxidase (MAO)–inhibiting chemistry, the pharmaceutical industry came into being activity, led to a series of MAO inhibitor antidepressants at the end of the 19th century (2). including phenelzine (Nardil) and tranylcypromine (Parnate), which are still used clinically. Soon after, The 20th Century and the Pharmaceutical Industry the first dibenzazepine (tricyclic) antidepressant imipra- mine was introduced by Ciba-Geigy Corporation in 1957 a Diseases of protozoal and spirochetal origin responded series of tricyclic compounds synthsized initially as struc- to synthetic chemotherapeutic agents. Interest in syn- tural analogs of phenothiazines, were developed. The tri- thetic chemicals that could inhibit the rapid repro- cyclic antidepressants are not antipsychotic, but instead duction of pathogenic bacteria and enable the host elevate mood by blocking the transport inactivation of organism to cope with invasive bacteria was dramatically monoamine neurotransmitters including norepineph- increased when the red dyestuff 2,4-diaminoazobenzene- rine and serotonin. In the late 1980s, a series of selec- 4′-sulfonamide (Prontosil) reported by Gerhard Domagk tive serotonin reuptake or transport inhibitors (SSRIs) dramatically cured dangerous systemic gram-positive bac- were developed, starting with R,S-zimelidine from Astra terial infections in man and animals. The observation by Pharmaceutica (which proved to be toxic) and then R,S- Woods and Fildes in 1940 that the bacteriostatic action of fluoxetine (Prozac) from Eli Lilly and Company, the first sulfonamide-like drugs is antagonized by p-aminobenzoic commercially successful SSRI and the first psychotropic acid is one of the early examples in which a balance of agent to attain an annual market above $1 billion. stimulatory and inhibitory properties depends on the The antianxiety agents, including a large series of structural analogies of chemicals. benzodiazepines (including chlordiazepoxide [Librium] That, together with the discovery of penicillin by and diazepam [Valium] and the carbamate meprobamate Alexander Fleming in 1929 and its subsequent exami- [Miltown]), are examples of the serendipitous discovery nation by Howard Florey and Ernst Chain in 1941, led of new drugs based on random screening of newly syn- to a water-soluble powder of much higher antibacterial thesized chemicals (Fig. 1). The discovery of these drugs potency and lower toxicity than that of previously known was based on observations of effects on the behavior of synthetic chemotherapeutic agents. With the discovery animals used in screening bioassays. In 1946, Frank M. of a variety of highly potent anti-infective agents, a sig- Berger observed unusual and characteristic paralysis and nificant change was introduced into medical practice. relaxation of voluntary muscles in laboratory animals for different series of compounds. At this point, the treat- DEVELOPMENTS LEADING TO VARIOUS ment of ambulatory anxious patients with meprobamate MEDICINAL CLASSES OF DRUGS and psychotic patients with one of the aminoalkylpheno- thiazine drugs was possible. Psychopharmacologic Agents and the Era of Brain There was a need for drugs of greater selectivity in Research the treatment of anxiety because of the side effects often Psychiatrists have been using agents active in the central nervous system for hundreds of years. Stimulants and depressants were used to modify the mood and mental HN CH3 states of psychiatric patients. Amphetamine, sedatives, S O O N and hypnotics were used to stimulate or depress the H2N O O NH2 HCl mental states of patients. Was it the synthesis of chlor- N Cl Cl N CH3 O promazine by Paul Charpentier that caused a revolution N HCl in the treatment of schizophrenia? Who really discovered CH3 chlorpromazine? Was it Charpentier, who first synthe- sized the molecule in 1950 at Rhone-Poulenc’s research Chlorpromazine HCl Meprobamate Chlordiazepoxide HCl (Thorazine) (Miltown) (Librium) laboratory; Simone Courvoisier, who reported distinc- tive effects on animal behavior; Henri Laborit, a French FIGURE 1 Psychopharmacologic agents. Kaduse.com Lemke_Historical Perspective.indd 2 12/9/2011 12:31:02 AM  HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY 3 encountered with phenothiazines. Leo Sternback, a I O O HO I C HO I C chemist working in the research laboratory of Hoffman-La OH OH Roche in New Jersey, decided to reinvestigate a relatively I O NH2 I O NH2 unexplored class of compounds that he had studied I I in the 1930s when he was a postdoctoral fellow at the University of Cracow in Poland. He synthesized about L-Thyroxine (T 4) L-Liothyronine (T 3) 40 compounds in this series, all of which were disappoint- ing in pharmacologic tests, so the project was abandoned. S S In 1957, during a cleanup of the laboratory, one com- Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH 2 pound synthesized 2 years earlier had crystallized and Vasopressin was submitted for testing to L.O. Randall, a pharmacolo- gist. Shortly thereafter, Randall reported that this com- S S pound was hypnotic and sedative and had antistrychnine effects similar to those of meprobamate. The compound Cys-Tyr-Iie-Gln-Asn-Cys-Pro-Leu-Gly-NH2 was named chlordiazepoxide and marketed as Librium Oxytocin in 1960, just 3 years after the first pharmacologic obser- FIGURE 2 Hormones from the endocrine glands. vations by Randall. Structural modifications of benzodi- azepine derivatives were undertaken, and a compound 5 to 10 times more potent than chlordiazepoxide was synthesized in 1959 and marketed as diazepam (Valium) sources. Frederick G. Banting and Charles H. Best, work- in 1963. The synthesis of many other experimental ana- ing in the laboratory of John J.R. McLeod at the University logs soon followed, and by 1983, about 35 benzodiaze- of Toronto, isolated the peptide hormone and began pine drugs were available for therapy (see Chapter 15). testing it in dogs. By 1922, researchers, with the help of Benzodiazepines are used in the pharmacotherapy of James B. Collip and the pharmaceutical industry, puri- anxiety and related emotional disorders and in the treat- fied and produced animal-based insulin in large quanti- ment of sleep disorders, status epilepticus, and other ties. Insulin soon became a major product for Eli Lilly convulsive states. They are used as centrally acting muscle & Co. and Novo Nordisk, a Danish pharmaceutical com- relaxants, for premedication, and as inducing agents in pany. In 1923, McLeod and Bunting were awarded the anesthesiology. Nobel Prize in Medicine or Physiology, and after much controversy, they shared the prize with Collip and Best. Endocrine Therapy and Steroids For the next 60 years, cattle and pigs were the major The first pure hormone to be isolated from the endo- sources of insulin. With the development of genetic crine gland was epinephrine, which led to further engineering in the 1970s, new opportunities arose for molecular modifications in the area of sympathomi- making synthetic insulin that is chemically identical to metic amines. Subsequently, norepinephrine was also human insulin. In 1978, the biotech company Genentech identified from sympathetic nerves. The development and the City of Hope National Medical Center produced of chromatographic techniques allowed the isolation human insulin in the laboratory using recombinant and characterization of a multitude of hormones from DNA technology. By 1982, Lilly’s Humulin became the a single gland. In 1914, biochemist Edward Kendall first genetically engineered drug approved by the U.S. isolated thyroxine from the thyroid gland. He subse- Food and Drug Administration (FDA). At about the same quently won the Nobel Prize in Physiology or Medicine time, Novo Nordisk began selling the first semisynthetic in 1950 for his discovery of the activity of cortisone. Two human insulin made by enzymatically converting por- of the hormones of the thyroid gland, thyroxine (T4) cine insulin. Novo Nordisk was also using recombinant and liothyronine (T3), have similar effects in the body technology to produce insulin. Recombinant insulin was regulating metabolism, whereas the two hormones from a significant milestone in the development of genetically the posterior pituitary gland—vasopressin, which exerts engineered drugs and combined the technologies of the pressor and antidiuretic activity, and oxytocin, which biotech companies with the know-how and resources stimulates lactation and uterine motility—differ consid- of the major pharmaceutical industries. Inhaled insu- erably both in their chemical structure and physiologic lin was approved by the FDA in 2006. Many drugs are activity. (Fig. 2) now available (see Chapter 27) to treat the more com- Less than 50 years after the discovery of oxytocin by mon type 2 diabetes in which insulin production needs Henry Dale in 1904, who found that an extract from the to be increased. Insulin had been the only treatment human pituitary gland contracted the uterus of a preg- for type 1 diabetes until 2005 when the FDA approved nant cat, the biochemist Vincent du Vigneud synthesized Amylin Pharmaceuticals’ Symlin to control blood sugar the cyclic peptide hormone. His work resulted in the levels in combination with the peptide hormone. The Nobel Prize in Chemistry in 1955. isolation and purification of several peptide hormones A major achievement in drug discovery and develop- of the anterior pituitary and hypothalamic-releasing hor- ment was the discovery of insulin in 1921 from animal mones now make it possible to produce synthetic peptide Kaduse.com Lemke_Historical Perspective.indd 3 12/9/2011 12:31:02 AM  4 HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY agonists and antagonists that have important diagnostic 100 million women worldwide were using oral contracep- and therapeutic applications. tive pills. In 1993, the British weekly The Economist con- Extensive and remarkable advances in the endocrine sidered the pill to be one of the seven wonders of the field have been made in the group of steroid hormones. modern world, bringing about major changes in the eco- The isolation and characterization of minute amounts of nomic and social structure of women globally. the active principles of the sex glands and from the adre- In the early 1930s, chemists recognized the similarity nal cortex eventually led to their total synthesis. Male of a large number of natural products including the adre- and female sex hormones are used in the treatment of nocortical steroids such as hydrocortisone. The medici- a variety of disorders associated with sexual development nal value of Kendall’s Compound F and Reichstein’s and the sexual cycles of males and females, as well as in Compound M was quickly recognized. The 1950 Nobel the selective therapy of malignant tumors of the breast Prize in Physiology or Medicine was awarded to Phillip S. and prostate gland. Synthetic modifications of the struc- Hench, Edward C. Kendall, and Tadeus Reichstein “…for ture of the male and female hormones have furnished their discovery relating to the hormones of the adrenal improved hormonal compounds such as the anabolic cortex, their structure and biological effects.” agents (see Chapter 40). Since early days, women have An interesting development in the study of gluco- ingested every manner of substance as birth control corticoids led in 1980 to the synthesis of the “abortion agents. In the early 1930s, Russell Marker found that, for pill,” Ru-486, synthesized by Etienne-Emile Beaulieu, hundreds of years, Mexican women had been eating wild a consultant to the French pharmaceutical company, yams of the Dioscorea genus for contraception, with appar- Rousel-Uclaf. Researchers at that time were investigating ent success. Marker determined that diosgenin is abun- glucocorticoid antagonists for the treatment of breast dant in yams and has a structure similar to progesterone. cancer, glaucoma, and Cushing syndrome. In screening Marker was able to convert diosgenin into progesterone, RU-486, researchers at Rousel-Uclaf found that it had a substance known to stop ovulation in rabbits. However, both antiglucocorticoid activity as well as high affinity progesterone is destroyed by the digestive system when for progesterone receptors where it could be used for ingested. In 1950, Carl Djerassi, a chemist working at the fertility control. RU-486, also known as mifepristone Syntex Laboratories in Mexico City, synthesized noreth- (Mifeprex), entered the French market in 1988, but indrone, the first orally active contraceptive steroid, by sales were suspended by Rousel-Uclaf when antiabortion a subtle modification of the structure of progesterone. groups threatened to boycott the company. In 1994, the Gregory Pincus, a biologist working at the Worcester company donated the United States rights to the New Foundation for Experimental Biology in Massachusetts York City–based Population Council, a nonprofit repro- studied Djerassi’s new steroid together with its double ductive and population control research institution. bond isomer norethynodrel (Fig. 3). Mifepristone is now administered in doctors’ offices as By 1956, clinical studies led by John Rock, a gynecol- a tablet in combination with misoprostol, a prostaglan- ogist, showed that progesterone, in combination with din that causes uterine contractions to help expel the norethindrone, was an effective oral contraceptive. G.D. embryo. The combination of mifepristone and miso- Searle was the first on the market with Enovid, a combi- prostol is more than 90% effective. Plan B, also known nation of mestranol and norethynodrel. In 2005, it was as the “morning after pill,” has been referred to as an estimated that 11 million American women and about emergency contraceptive. It contains levonorgestrel, the same progestin that is in “the pill,” and should be taken within 3 days of unprotected sex and can reduce the risk of pregnancy by 89%. O CH3 H3C H3C OH H3C OH Anesthetics and Analgesics C CH C CH H3C H H H H The first use of synthetic organic chemicals for the mod- ulation of life processes occurred when nitrous oxide, H H H H H H O O O ether, and chloroform were introduced in anesthesia during the 1840s. Horace Wells, a dentist in Hartford, Progesterone Norethindrone Norethynodrel Connecticut, administered nitrous oxide during a tooth CH3 extraction while Crawford Long, a Georgia physician, H3C N used ether as an anesthetic for excising a growth on a H3C OH H3C OH C CH C C CH3 patient’s neck. It was William Morton, a 27-year-old den- H H tist, however, who gave the first successful public demon- H H H stration of surgical anesthesia on October 16, 1846, at the CH3O O surgical amphitheater that is now called the Ether Dome at Massachusetts General Hospital. Morton attempted to Mestranol Mifepristone patent his discovery but was unsuccessful, and he died (RU 486) penniless in 1868. Chloroform had also been used as an anesthetic at St. Bartholomew’s Hospital in London. In FIGURE 3 Steroidal agents. Kaduse.com Lemke_Historical Perspective.indd 4 12/9/2011 12:31:02 AM  HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY 5 Paris, France, Pierre Fluorens tested both chloroform receptors. In 1973, Avram Goldstein, Solomon Snyder, and ethyl chloride as anesthetics in animals. Ernst Simon, and Lars Terenius independently described The potent and euphoric properties of the extract saturable, stereospecific binding sites for opiate drugs in of the opium poppy have been known for thousands of the mammalian nervous system. Shortly thereafter, John years. In the 16th century, the Swiss physician and alche- Hughes and Hans Kosterlitz, working at the University of mist, Paracelsus (1493–1541) popularized the use of Aberdeen in Scotland, described the isolation from pig opium in Europe. At that time, an alcoholic solution of brains of two pentapeptides that exhibited morphine-like opium, known as laudanum, was the method of admin- actions on the guinea pig ileum. At about the same time, istration. Morphine was first isolated in pure crystalline Goldstein reported the presence of peptide-like sub- form from opium by the German apothecary, Fredrick stances in the pituitary gland showing opiate-like activ- W. Sertürner, in 1805 who named the compound “mor- ity. Subsequent research revealed that there are three phium” after Morpheus, the Greek god of dreams. It distinct families of opiate peptides: the enkephalins, the took another 120 years before the structure of morphine endorphins, and the dynorphins. was elucidated by Sir Robert Robinson at the University of Oxford. The chemistry of morphine and the other Hypnotics and Anticonvulsants opium alkaloids obtained from Papaver somniferum has Since antiquity, alcoholic beverages and potions con- fascinated and occupied chemists for over 200 years, taining laudanum, an alcoholic extract of opium, and resulting in many synthetic analgesics available today various other plant products have been used to induce (see Chapter 20). (−)-Morphine was first synthesized by sleep. Bromides were used in the middle of the 19th Marshall Gates at the University of Rochester in 1952. century as sedative-hypnotics, as were chloral hydrate, Although a number of highly effective stereoselective paraldehyde, urethane, and sulfenal. Joseph von synthetic pathways have been developed, it is unlikely Merring, on the assumption that a structure having that a commercial process can compete with its isola- a carbon atom carrying two ethyl groups would have tion from the poppy. Diacetylmorphine, known as her- hypnotic properties, investigated diethyl acetyl urea, oin, is highly addictive and induces tolerance. The illicit which proved to be a potent hypnotic. Further investiga- worldwide production of opium now exceeds the phar- tions led to 5,5-diethylbarbituric acid, a compound syn- maceutical production by almost 10-fold. In the United thesized 20 years earlier in 1864 by Adolph von Beyer. States, some 800,000 people are chemically addicted to Phenobarbital (5-ethyl-5-phenylbarbituric acid) (Fig. 4) heroin, and a growing number are becoming addicted to was synthesized by the Bayer Pharmaceutical Company OxyContin, a synthetic opiate also known as oxycodone. and introduced to the market under the name Luminol. Another synthetic opiate, methadone, relaxes the craving The compound was effective as a hypnotic, but also for heroin or morphine. A series of studies in the 1960s exhibited properties as an anticonvulsant. The success of at Rockefeller University by Vincent Dole and his wife, phenobarbital led to the testing of more than 2,500 bar- Marie Nyswander, found that methadone could also be a biturates, of which about 50 were used clinically, many viable maintenance treatment to keep addicts from her- of which are still in clinical use. Modification of the bar- oin. It is estimated that there are about 250,000 addicts bituric acid molecule also led to the development of the taking methadone in the United States. It has not been hydantoins. Phenytoin (also known as diphenylhydantoin widely recognized in the United States that opiate addic- or Dilantin) (Fig. 4) was first synthesized in 1908, but its tion is a medical condition for which there is no known anticonvulsant properties were not discovered until 1938. cure. More than 80% of United States heroin addicts still Because phenytoin was not a sedative at ordinary doses, it lack access to methadone treatment facilities, primarily established that antiseizure drugs need not induce drows- due to the stigma against drug users and the medical dis- iness and encouraged the search for drugs with selective tribution of methadone. antiseizure action. It has been only within the last 40 years that scientists have begun to understand the effects of opioid analgesics Local Anesthetics at the molecular level. Beckett and Casey at the University The local anesthetics can be traced back to the naturally of London proposed in 1954 that opiate effects were recep- occurring alkaloid cocaine isolated from Erythroxylon tor mediated, but it was not until the early 1970s that the coca. A Viennese ophthalmologist, Carl Koller, had stereospecific binding of opiates to specific receptors was demonstrated. The characterization and classification of three different types of opioid receptors, mu, kappa, and H delta, by William Martin formed the basis of our current O N O H understanding of opioid pharmacology. The demonstra- NH N O tion of stereospecific binding of radiolabeled ligands to O NH opioid receptors led to the development of radiorecep- O tor binding assays for each of the opioid receptor types, Phenobarbital Phenytoin a technique that has been of major importance in the identification of selective opioids as well as many other FIGURE 4 Kaduse.com Examples of an early hypnotic and anticonvulsant. Lemke_Historical Perspective.indd 5 12/9/2011 12:31:03 AM  6 HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY experimented with several hypnotics and analgesics for as digoxin. This is now the most widely used cardiac use as a local anesthetic in the eye. His friend, Sigmund glycoside. Today, dried foxglove leaves are processed to Freud, suggested that they attempt to establish how yield digoxin much like the procedure used by Withering. the South American Indians allayed fatigue by chew- It takes about 1,000 kg of dried foxglove leaves to make ing leaves of the coca bush. Cocaine had been isolated 1 kg of pure digitalis. from the plant by the Swedish chemist Albert Niemann It is the group of drugs used in the therapy of hyper- at Gothenburg University in 1860. Koller found that cholesterolemia that has received the greatest success cocaine numbed the tongue, and thus, he discovered a and financial reward for the pharmaceutical industry local anesthetic. He quickly realized that cocaine was an during the last two decades. Cholesterol-lowering drugs, effective, nonirritating anesthetic for the eye, leading to known as statins, are one of the cornerstones in the pre- the widespread use of cocaine in both Europe and the vention of both primary and secondary heart diseases. United States. (Carl Koller’s nickname among Viennese Drugs such as Merck’s lovastatin (Mevacor) and Pfizer’s medical students was “Coca Koller”). Richard Willstatter atorvastatin (Lipitor) are a huge success (Fig. 6). In in Munich determined the structure of both cocaine and 2004, Lipitor was the world’s top selling drug, with sales atropine in 1898 and succeeded in synthesizing cocaine of more than $10 billion. As a class, cholesterol- and 3 years later. Although today cocaine is of greater his- triglyceride-lowering drugs were the world’s top selling toric than medicinal importance and is widely abused, category, with sales exceeding $30 billion. The discovery few developments in the chemistry of local anesthetics of the statins can be credited to Akira Endo, a research can disclaim a structural relationship to cocaine (Fig. 5). scientist at Sankyo Pharmaceuticals in Japan (3). Endo’s Benzocaine, procaine, tetracaine, and lidocaine all can 1973 discovery of the first anticholesterol drug has be considered structural analogs of cocaine, a classic almost been relegated to obscurity. The story of his example of how structural modification of a natural research and the discovery of lovastatin are not typical product can lead to useful therapeutic agents. but often escape attention. When Endo joined Sankyo after his university studies to investigate food ingredients, Drugs Affecting Renal and Cardiovascular Function he searched for a fungus that produced an enzyme to Included in this category are drugs used in the treatment make fruit juice less pulpy. The search was a success, and of myocardial ischemia, congestive heart failure, vari- Endo’s next assignment was to find a drug which would ous arrhythmias, and hypercholesterolemia. Only two block the enzyme hydroxymethylglutaryl-coenzyme A examples of drug development will be highlighted. Use (HMG-CoA) a key enzyme essential to the production of the cardiac drug digoxin dates back to the folk remedy of cholesterol. With Endo’s interest and background, he foxglove attributed to William Withering who, in 1775, searched for fungi that would block this enzyme. In 1973, discovered that the foxglove plant, Digitalis purpurea, after testing 6,000 fungal broths Endo found a substance was beneficial to those suffering from abnormal fluid made by the mold Penicillium citrinum that was a potent buildup. The active principles of digitalis were isolated inhibitor on the enzyme needed to make cholesterol; it in 1841 by E. Humolle and T. Quevenne in Paris. They was named compactin (mevastatin) (Fig. 6). However, consisted mainly of digitoxin. The other glycosides of the substance did not work in rats but did work in hens digitalis were subsequently isolated in 1869 by Claude A. and dogs. Endo’s bosses were unenthusiastic about Nativelle and in 1875 by Oswald Schmiedberg. The cor- his discovery and discouraged further research with this rect structure of digitoxin was established more than 50 compound. With the collaboration of Akira Yamamoto, years later by Adolf Windaus at Gothenburg University. a physician treating patients with extremely high cho- In 1929, Sydney Smith at Burroughs Wellcome isolated lesterol due to a genetic defect, Endo prepared samples and separated a new glycoside from D. purpurea, known of his drug, and it was administered to an 18-year-old CH3 N HO O HO HO COOCH3 CO2H CO2H H H2N CO2C2H5 O OH OH O O O H H H F H O O O H H N Cocaine Benzocaine H N CH3 R HO O H2N CO2(CH2)2N(C2H5)2 NHCOCH 2N(C2H5)2 CH3 Pravastatin Atorvastatin R = H; Compactin (Pravachol) (Lipitor) (Mevastatin) Procaine Lidocaine R = CH3; Lovastatin (Mevacor) FIGURE 5 Synthetic local anesthetics development based on the structure of cocaine. FIGURE 6 The first statins. Kaduse.com Lemke_Historical Perspective.indd 6 12/9/2011 12:31:03 AM  HISTORY AND EVOLUTION OF MEDICINAL CHEMISTRY 7. woman by Yamamoto. Further testing in nine patients.ccoomm many types of cancer, primarily testicular, ovarian, blad- uu see led to an average of 27% lowering of cholesterol. In s 1978, using a different fungus, Merck discovered a sub- der, lung, and stomach cancers. Cisplatin is now the gold standard against which new medicines are compared. It dd stance that was nearly identical to Endo’s; this one was was first synthesized in 1845, and its structure was eluci- aa