The Organic Chemistry of Drug Design and Drug Action

Richard B. Silverman

• Publisher: Academic Press
• Year: 2012
• ISBN:
  9780080513379
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

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

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, ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Dedication
• Copyright
• Preface to the First Edition
• Preface to the Second Edition
• Chapter 1: Introduction
• Chapter 2: Drug Discovery, Design, and Development
• Chapter 3: Receptors
• Chapter 4: Enzymes
• Chapter 5: Enzyme Inhibition and Inactivation
• Chapter 6: DNA-Interactive Agents
• Chapter 7: Drug Metabolism
• Chapter 8: Prodrugs and Drug Delivery Systems
• Appendix: Answers to Chapter Problems
• Index