Organic Chemistry of Drug Design and Drug Action (eBook)

Richard B. Silverman (Autor)

eBook Download: PDF | EPUB

2012 | 2. Auflage
617 Seiten
Elsevier Science (Verlag)
978-0-08-051337-9 (ISBN)

Infos

Standard medicinal chemistry courses and texts are organized by classes of drugs with an emphasis on descriptions of their biological and pharmacological effects. This book represents a new approach based on physical organic chemical principles and reaction mechanisms that allow the reader to extrapolate to many related classes of drug molecules. The Second Edition reflects the significant changes in the drug industry over the past decade, and includes chapter problems and other elements that make the book more useful for course instruction. - New edition includes new chapter problems and exercises to help students learn, plus extensive references and illustrations - Clearly presents an organic chemist's perspective of how drugs are designed and function, incorporating the extensive changes in the drug industry over the past ten years - Well-respected author has published over 200 articles, earned 21 patents, and invented a drug that is under consideration for commercialization

Professor Richard B. Silverman received his B.S. degree in chemistry from The Pennsylvania State University in 1968 and his Ph.D. degree in organic chemistry from Harvard University in 1974 (with time off for a two-year military obligation from 1969-1971). After two years as a NIH postdoctoral fellow in the laboratory of the late Professor Robert Abeles in the Graduate Department of Biochemistry at Brandeis University, he joined the chemistry faculty at Northwestern University. In 1986, he became Professor of Chemistry and Professor of Biochemistry, Molecular Biology, and Cell Biology. In 2001, he became the Charles Deering McCormick Professor of Teaching Excellence for three years, and since 2004 he has been the John Evans Professor of Chemistry. His research can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents acting on enzymes and receptors. His awards include DuPont Young Faculty Fellow (1976), Alfred P. Sloan Research Fellow (1981-1985), NIH Research Career Development Award (1982-1987), Fellow of the American Institute of Chemists (1985), Fellow of the American Association for the Advancement of Science (1990), Arthur C. Cope Senior Scholar Award of the American Chemical Society (2003), Alumni Fellow Award from Pennsylvania State University (2008), Medicinal Chemistry Hall of Fame of the American Chemical Society (2009), the Perkin Medal from the Society of Chemical Industry (2009), the Hall of Fame of Central High School of Philadelphia (2011), the E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society (2011), Fellow of the American Chemical Society (2011), Sato Memorial International Award of the Pharmaceutical Society of Japan (2012), Roland T. Lakey Award of Wayne State University (2013), BMS-Edward E. Smissman Award of the American Chemical Society (2013), the Centenary Prize of the Royal Society of Chemistry (2013), and the Excellence in Medicinal Chemistry Prize of the Israel Chemical Society (2014). Professor Silverman has published over 320 research and review articles, holds 49 domestic and foreign patents, and has written four books (The Organic Chemistry of Drug Design and Drug Action is translated into German and Chinese). He is the inventor of LyricaTM, a drug marketed by Pfizer for epilepsy, neuropathic pain, fibromyalgia, and spinal cord injury pain; currently, he has another CNS drug in clinical trials.

Textauszug

Chapter 1

Introduction

Publisher Summary

Medicinal chemistry is the science that deals with the discovery and design of new therapeutic chemicals and their development into useful medicines. Medicinal chemistry involves isolation of compounds from the nature or the synthesis of new molecules; investigations of the relationships among the structure of natural and/or synthetic compounds and their biological activities; elucidations of their interactions with receptors of various kinds, including enzymes and DNA; the determination of their absorption, transport, and distribution properties; and studies of the metabolic transformations of these chemicals into other chemicals and their excretion. For ages, nature has been an excellent source of new drugs or precursors to drugs. Human beings have searched for cures for illnesses by chewing herbs, berries, roots, and barks. When a natural product is found to be active, it is chemically modified to improve its properties. Greater than 60% of the anticancer and anti-infective agents that are on the market or in clinical trials are of natural product origin or derived from natural products. This is a result of the inherent nature of secondary metabolites of plants that act in defense of their producing organisms.

1.1 Medicinal Chemistry Folklore

1.2 Discovery of New Drugs

1.3 General References

1.4 References

1.1 Medicinal Chemistry Folklore

Medicinal chemistry is the science that deals with the discovery and design of new therapeutic chemicals and their development into useful medicines. Medicines are substances used to treat diseases. Drugs are molecules used as medicines or as components in medicines to diagnose, cure, mitigate, treat, or prevent disease.[1] Medicinal chemistry may involve isolation of compounds from Nature or the synthesis of new molecules, investigations of the relationships between the structure of natural and/or synthetic compounds and their biological activities, elucidations of their interactions with receptors of various kinds, including enzymes and DNA, the determination of their absorption, transport, and distribution properties, and studies of the metabolic transformations of these chemicals into other chemicals and their excretion. More recently, genomics, the investigations of an organism’s genome (all of the organism’s genes) to identify important target genes and gene products (that is, proteins expressed by the genes), and proteomics, the investigations of new proteins in the organism’s proteome (all of the proteins expressed by the genome)[2] to determine their structure and/or function often by comparison with known proteins, have become increasingly important approaches to identify new drug targets.

Medicinal chemistry, in its crudest sense, has been practiced for several thousand years. Man has searched for cures for illnesses by chewing herbs, berries, roots, and barks. Some of these early clinical trials were quite successful; however, not until the last 100–150 years has knowledge of the active constituents of these natural sources been known. The earliest written records of the Chinese, Indian, South American, and Mediterranean cultures described the therapeutic effects of various plant concoctions.[3–5] A Chinese health science anthology called Nei Ching is thought to have been written by the Yellow Emperor in the 13th century B.C., although some believe that it was backdated by the 3rd-century compilers.[6] The Assyrians described on 660 clay tablets 1000 medicinal plants used from 1900−400 B.C.

Two of the earliest medicines were described about 5100 years ago by the Chinese Emperor Shen Nung in his book of herbs called Pen Ts’ao.[7] One of these is Ch’ang Shan, the root Dichroa febrifuga, which was prescribed for fevers. This plant contains alkaloids that are used even today in the treatment of malaria. Another plant called Ma Huang (now known as Ephedra sinica) contains ephedrine, a drug that raises the blood pressure and relieves bronchial spasms; this herb was used as a heart stimulant, a diaphoretic agent (perspiration producer), and for treatment of asthma, hay fever, and nasal and chest congestion. It also is used today (unadvisably) by some body builders and endurance athletes because it promotes themogenesis (the burning of fat) by release of fatty acids from stored fat cells, leading to quicker conversion of the fat into energy. Ephedra also tends to increase the contractile strength of muscle fibers, which allows body builders to work harder with heavier weights.

Theophrastus in the 3rd-century B.C. mentioned opium poppy juice as an analgesic agent, and in the 10th-century A.D. Rhazes (Persia) introduced opium pills for coughs, mental disorders, aches, and pains. The opium poppy, Papaver somniferum, contains morphine, a potent analgesic agent and codeine, which is prescribed today as a cough suppressant. The East Asians and the Greeks used henbane, which contains scopolamine (truth serum) as a sleep inducer. Inca mail runners and silver miners in the high Andean mountains chewed coca leaves (cocaine) as a stimulant and euphoric. The antihypertensive drug reserpine was extracted by ancient Hindus from the snakelike root of the Rauwolfia serpentina plant and was used to treat hypertension, insomnia, and insanity. Alexander of Tralles in the 6th-century A.D. recommended the autumn crocus (Colchicum autumnale) for relief of pain of the joints, and it was used by Avrienna (11th-century Persia) and by Baron Anton von Storck (1763) for the treatment of gout. Benjamin Franklin heard about this medicine and brought it to America. The active principle in this plant is the alkaloid colchicine, which is used today to treat gout.

In 1633 a monk named Calancha, who accompanied the Spanish Conquistadors to Central and South America, introduced one of the greatest herbal medicines to Europe on his return. The South American Indians would extract the cinchona bark and use it for chills and fevers; the Europeans used it for the same and for malaria. In 1820 the active constituent was isolated and later determined to be quinine, an antimalarial drug.

Modern therapeutics is considered to have begun with an extract of the foxglove plant, which was cited by Welsh physicians in 1250, named by Fuchsius in 1542, and introduced for the treatment of dropsy (now called congestive heart failure) in 1785 by Withering.[3,8] The active constituents are secondary glycosides from Digitalis purpurea (the foxglove plant) and Digitalis lanata, namely, digitoxin and digoxin, respectively, both important drugs for the treatment of congestive heart failure. Today, digitalis, which refers to all of the cardiac glycosides, is still manufactured by extraction of foxglove and related plants.

1.2 Discovery of New Drugs

Nature is still an excellent source of new drugs or, more commonly, of precursors to drugs. Of the 20 leading drugs in 1999,9 of them were derived from natural products.[9] Almost 40% of the 520 new drugs approved for the drug market between 1983 and 1994 were natural products or derived from natural products. Greater than 60% of the anticancer and anti-infective agents that are on the market or in clinical trials are of natural product origin or derived from natural products.[10] This may be a result of the inherent nature of these secondary metabolites to act in defense of their producing organisms; for instance, a fungal natural product might be produced against bacteria or other fungi or against cell replication of foreign organisms.[11]

Typically, when a natural product is found to be active, it is chemically modified to improve its properties. As a result of advances made in synthesis and separation methods and in biochemical techniques since the late 1940s, the early random approach to drug discovery (Figure 1.1) was supplanted by a more rational approach, namely, one that involves the element of design. A discussion of how drugs are discovered and chemically modified to improve or change their medicinal properties is presented in Chapter 2. As we will see, the random approach still is important!

Figure 1.1 “That’s Dr Arnold Moore. He’s conducting an experiment to test the theory that most great scientific discoveries were hit on by accident.” Drawing by Hoff; © 1957, The New Yorker Magazine, Inc.

1.3 General References

The following references are excellent sources of material for this entire book.

Journals

Annual Reports in Medicinal Chemistry;

Academic Press, San Diego

Annual Review of Biochemistry

Annual Review of Medicinal Chemistry

Biochemical Pharmacology

Bioorganic and Medicinal Chemistry

Bioorganic and Medicinal Chemistry Letters

Chemistry & Biology

Current Drug Metabolism

Current Drug Targets

Current...

Produkt-Details

• Erscheint lt. Verlag: 2.12.2012
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie ► Organische Chemie
• Themenwelt: Technik
• ISBN-10: 0-08-051337-9 / 0080513379
• ISBN-13: 978-0-08-051337-9 / 9780080513379