The Practice of Medicinal Chemistry

Camille Georges Wermuth

• Publisher: Academic Press
• Year: 2003
• eBook ISBN: 9780080497778
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Toxicology

The Practice of Medicinal Chemistry, 2E, is a single-volume source on the practical aspects of medicinal chemistry. The successful first edition was nicknamed "The Bible" by medicinal chemists, and the second edition has been updated, expanded and refocused to reflect developments over the last decade. Emphasis is put on how medicinal chemists conduct their search for and design of new drug entities. In contrast to competing books, it focuses on the chemistry rather than pharmacological concepts or descriptions of the various therapeutic classes of drugs. Most medicinal chemists working in the pharmaceutical industry are organic synthetic chemists who must acquire a strong knowledge of medicinal chemistry as they enter the industry. This book aims to be their practical handbook - a complete guide to the drug discovery process. - The only book available dealing with the practical aspects of medicinal chemistry - Serves as a complete guide to the drug discovery process, from conception of the molecules to drug production - Updated chapters devoted to the discovery of new lead compounds, including combinatorial chemistry

Part I

General Aspects of Medicinal Chemistry

1 A BRIEF HISTORY OF DRUGS: FROM PLANT EXTRACTS TO DNA TECHNOLOGY

François Chast^*,

I. The ancient link between medicine and religion

II. Modern chemistry as the basis of the concept of modern drugs

III. The birth of organic chemistry

IV. The extraction of alkaloids from plants

V. Salicylates and aspirin: the first best-seller

VI. First drugs for the heart

VII. Treatment for hypertension as a disease

VIII. General and local anaesthesia

IX. Antiepileptic drugs

X. Fight against microbes

XI. Sulfonamides

XII. Antibiotics

XIII. Aids: an emerging disease

XIV. Drugs for endocrine disorders

XV. Drugs of the mind

XVI. Drugs for immunosuppression

XVII. Chemistry against cancer

XVIII. From genetics to DNA technology

XIX. Conclusion

References

Le médicament place l’organisme dans des conditions particulières qui en modifient heureusement les procédés physiques et chimiques lorsqu’ils ont été troublés.

Claude Bernard^**

I THE ANCIENT LINK BETWEEN MEDICINE AND RELIGION

The earliest written records of therapeutic practices are to be found in the Ebers Papyrus, dating from the sixteenth century BC. This is historically of value, since by itself, it represents a compilation of earlier works that contain a large number (877) of prescriptions and recipes. Many plants are mentioned, including opium, cannabis, myrrh, frankincense, fennel, cassia, senna, thyme, henna, juniper, linseed, aloe, castor oil and garlic.¹ Cloves of garlic have been found in Egyptian burials, including the tomb of Tutankhamun and in the sacred underground temple of the bulls at Saqqara.² The Ebers Papyrus describes several charms and invocations that were used to encourage healing. The Egyptians were also well known for other healing techniques: spiritual healing, massage and surgery, as well as the extensive use of therapeutic herbs and foods. The Egyptian Shaman physician had to discover the nature of the particular entity possessing the person and then attack, drive it out, or otherwise destroy it. This was done by some powerful magic for which rituals, spells, incantations, talismans and amulets were used.

The art of divination is first known to be used in Babylonian-Assyrian medicine along with the use of astrology to determine the influence of the stellar constellations on human welfare and medical ethics. Two others aspects were usually outlined: besides divination, exorcism and medical treatment were blended together to form a composite picture. Two hundred and fifty vegetable drugs and 120 mineral drugs were identified in the clay tablets from the library of King Assurbanipal. Excrements likewise played an important part in the therapy. They were supposed to throw out the evil spirit that had invaded the body of the patient.³

Ancient civilizations tended to borrow and adopt the skills and knowledge of medicine and healing of various cultures to their own. When Alexander the Great conquered and encompassed virtually the known world, he did so with the intention of extolling the humanizing Greek culture.

All the nations brought under the wing of Greece, however, brought with them their own traditions and customs including their healing knowledge.⁴

Hippocrates (approximately 460–377 BC) is considered as the father of medicine through a major, but anonymous writing called Corpus Hippocraticum. The regulation of diet occupied the most important place in therapeutics. At his time, drugs were mainly from vegetal origin: juice of the poppy, henbane and mandrake are cited side by side with castor oil, fennel plant, linseed, juniper, saffron, etc. Aspects of the theoretical basis for their use and application were also adopted. Purgatives, sudorifics and emetics were frequently used in order to purify sick organisms. Just as the Greek universe was ordered according to the principles of four dynamic elements: fire, water, air and earth, Hippocrates saw the body as governed by four corresponding ‘humors’, consisting of: sanguine, melancholic, phlegmatic and choleric. Such theories, common to most ancient civilizations, outline essential differences between holistic objectives of traditional medicine in contrast to that of contemporary medicine.⁵ These principles, formulated 2400 years ago, attempted to weed out various aspects of superstition which dominated people’s minds at the time, in favour of applied logic and reason. Health and disease were seen as a question of humoral balance or imbalance with foods and herbs classified according to their ability to affect natural homeostasis. Of his many aphorisms the most memorable are: ‘above all else, do no harm’, or ‘let your medicine be your food and your food, medicine’. The classification of herbs as ‘hot, ‘cold’, ‘wet’, ‘dry’ for instance was not thought to represent absolutes in the scientific sense, but rather aspects to be utilized as part of the art of medicine.⁶

Ancient times were a period when poisoning was raised to a high art, and in turn spurred on dazzling efforts to discover or create effective antidotes. Thus the art of Greek pharmacy was strongly supported and encouraged by the wealthy. Mithridaticum was an antidote containing no less than 54 ingredients, developed for Mithridates, king of Pontus during the first century BC. The remedy consisted of small amounts of various poisons which taken over a period of time are supposed to make one immune to their fatal effects.⁷ The Romans, famous for incorporating the best of their Greek forbears, attempted through the efforts of Andromachus, Nero’s physician, to improve or at least enlarge upon Mithridatesshotgun anti-poison by increasing the number of toxic ingredients from 54 to 70. Under the name Theriac, it was described in pharmacopoeias for centuries, through the European Renaissance to the modern pharmacopoeias, at the end of the nineteenth century.

One of the most significant virtues of the Romans, responsible for the long-lasting success of their civilization, was their ability to adopt local customs, religions and cultural mores, along with incorporating the accumulated knowledge and wisdom of foreign cultures under Roman dominion.

The two most important medical figures of Rome, whose contributions remain the uncontested ‘standard’ for botany and medicine are Dioscorides and Galen.⁸ Dioscorides was born in Turkey, in the first century. His most significant contribution was the five botanical books entitled De Materia Medica,⁹ forming the basis for all subsequent Materia Medica for the next 1600 years throughout Europe.

Most of Dioscorides’ Materia Medica consists of plant medicines, while the remainder is divided more or less 10% mineral and 10% animal. If we consider that many chemically synthesized drugs were once derived from plant products, the percentages of Dioscorides’ work is remarkably similar to today’s. Dioscorides sought to classify drugs according to broad physiological categories of action, including: warming, mollifying and softening, astringent, bitter, or binding, diuretics, drying, etc. He raised herbal medicine beyond the purely empirical principle of finding a specific herb for a specific disease and presupposed a corresponding system of diagnosis for which the above physiologic actions will be useful. His work became the primary source of future herbalists for over 1500 years.

Galen, born in Sicily, lived around 130 AD, learned anatomy at the Greek School in Alexandria, and was the last of the important Greek herbalists, writing over 400 works, of which 83 ar...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Biography
• Contributors
• Foreword
• Preface to the First Edition
• Preface to the Second Edition
• Part I: General Aspects of Medicinal Chemistry
• Part II: Lead Compound Discovery Strategies
• Part III: Primary Exploration of Structure–Activity Relationships
• Part IV: Substituents and Functions: Qualitative and Quantitative Aspects of Structure–Activity Relationships
• Part V: Spatial Organization, Receptor Mapping and Molecular Modeling.
• Part VI: Chemical Modifications Influencing the Pharmacokinetic Properties
• Part VII: Pharmaceutical and Chemical Formulation Problems
• Part VIII: Development of New Drugs: Legal and Economic Aspects
• INDEX