Blass Basic Principles of Drug Discovery and Development

1. Auflage 2015
ISBN: 978-0-12-411525-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 580 Seiten

Basic Principles of Drug Discovery and Development presents the multifaceted process of identifying a new drug in the modern era, providing comprehensive explanations of enabling technologies such as high throughput screening, structure based drug design, molecular modeling, pharmaceutical profiling, and translational medicine, all areas that have become critical steps in the successful development of marketable therapeutics. The text introduces the fundamental principles of drug discovery and development, also discussing important drug targets by class, in vitro screening methods, medicinal chemistry strategies in drug design, principles in pharmacokinetics and pharmacodynamics, animal models of disease states, clinical trial basics, and selected business aspects of the drug discovery process. It is designed to enable new scientists to rapidly understand the key fundamentals of drug discovery, including pharmacokinetics, toxicology, and intellectual property.' - Provides a clear explanation of how the pharmaceutical industry works - Explains the complete drug discovery process, from obtaining a lead, to testing the bioactivity, to producing the drug, and protecting the intellectual propertyIdeal for anyone interested in learning about the drug discovery process and those contemplating careers in the industry - Explains the transition process from academia or other industries

As an industrial medicinal chemist, Dr. Blass has experience with major pharmaceutical organizations (Wyeth, Procter & Gamble Pharmaceuticals) and small biotech operations (Fox Chase Chemical Diversity Center), which provided him with a wealth of expertise in the art of drug discovery and development (including a wide range of disease states and biological targets). His position with Temple University's School of Pharmacy and the Moulder Center for Drug Discovery has provided him with essential experience as an educator and academic scientist. These experiences, as well as his training and expertise as a registered US patent agent, have provided him with the tools and skills necessary to bridge the gap between industrial drug discovery and academic research.

Autoren/Hrsg.

Blass, Benjamin E.

Leseproben

Chapter 2

The Drug Discovery Process

From Ancient Times to the Present Day

Abstract

The need to discover novel therapeutics for the treatment of diseases and conditions that afflict humanity has been a recognized issue for many centuries. Useful medications were certainly identified long before there was an understanding of the underlying science, but the process as a whole has changed substantially over time. Basic scientific discoveries, advances in applied science, and changes in the regulatory environment have all played a significant role in the evolution of the drug discovery and development process. The historical framework of the evolution of this process provides significant insight into how new drugs are discovered in the modern era, the role of key technologies, and how governmental oversight has impacted the pharmaceutical industry.

Keywords

Biotechnology; Chemoreceptors; High throughput technology; Preindustrial drug discovery; Recombinant DNA; Regulatory milestones; Transfection technology; Transgenic animal models

Throughout the course of history, there has been a near constant need for therapeutic intervention for the treatment of disease. Efforts to provide for this need can be traced to prehistoric times as evidenced in cave drawings from 7000 to 5000 BC that are suggestive of the use of hallucinogenic mushrooms. The concept that curing diseases or alleviating symptoms could be accomplished by eating, drinking, or applying substances to the body is ancient, but the methods used to discover therapeutic agents has changed dramatically over the course of human history. In its earliest form, from ancient times until the mid-nineteenth century, the identification of new drugs was primarily the result of serendipity, as the foundational science required for the systematic study of potential new therapeutic entities had not yet been established. Modern methods of drug discovery have evolved over the last two centuries, however, as a result of advances in basic science (e.g., chemistry, biology, pharmacology) and applied science (e.g., transgenic animal models, molecular modeling, robotics) leading to a process that is far less dependent upon the serendipitous identification of therapeutic agents. A third factor, governmental and regulatory oversight, which focuses primarily on ensuring the safety and efficacy of new medications, has also had a major impact on modern drug discovery over the last century. This chapter will review the evolution of the drug discovery process from ancient times to the modern age, focusing on key scientific advances and the regulatory environment that changed the way in which new drugs are identified.

The Age of Botanicals: Preindustrial Drug Discovery

The search for effective methods and medications designed to improve the quality and length of life predates the age of modern discovery by several thousand years. While it is unclear exactly when humanity began to understand that ingestion of specific materials (i.e., drugs) could influence physiology, disease-related or otherwise, there is evidence suggesting that these concepts were beginning to evolve as early as prehistoric times. Plant remains from between 7000 and 5500 BC found in the Spirit Caves of north-western Thailand included seeds of the betel nut, a mildly psychoactive agent, indirectly suggesting its use in the Neolithic period.1 Human consumption, perhaps for the alteration of perception, is also suggested by the presence of skeletal remains from 2680 BC in the presence of lime-containing betel nut shells found in the Duyong cave of the Philippines. Although not conclusive evidence of consumption, the presence of the lime and betel nuts is consistent with practices designed to aid in the absorption of the active ingredient (arecoline) while chewing that are still in practice in modern India.2 The prehistoric use of hallucinogenic mushrooms is also implicated by Saharan cave drawings (c.7000–5000 BC),3 suggesting that humanity became aware of the potency of these plants long before recorded history.

Direct evidence of the early identification of the most frequently consumed drug in history, alcohol, is far easier to obtain. Although it is unclear how the fermentation of alcoholic beverages was discovered, there is ample evidence indicating that its discovery occurred early in human history. Strong evidence exists indicating that alcoholic beverages were developed as early as the Neolithic period, and that its use was common across the ancient world.4 Given that the effects of alcohol consumption occurs rapidly upon ingestion, it is not surprising that various alcoholic beverages were among the first drugs to be widely consumed for either recreational or medicinal purposes.

When humanity began to recognize the medicinal properties of various plants and chemicals is also an open question. It is clear, however, that the pursuit of treatments for diseases and symptom relief is not a phenomenon of the modern world. The Mesopotamians documented their medical methods and prescriptions on stone tablets. One of the oldest and largest collections from this civilization consists of a series of 40 tablets from around 1700 BC that are collectively known as “Treatise of Medical Diagnosis and Prognoses.” Included among the writings are some of the earliest recorded uses of drugs for medicinal purposes (Figure 2.1(a)).5 In a similar fashion, the Ebers Papyrus was written by the ancient Egyptians around 1550 BC and contains several hundred “prescriptions” for the treatment of disease or symptomatic relief (Figure 2.1(b)).6 The origin of traditional Chinese medicine is largely unknown, but it is estimated that the practices and methods are at least 2000years old. The herbalist and acupuncturist Li Shih-chen completed the first draft of Pen-tsao Kang-mu, which is widely considered the most comprehensive text on traditional Chinese medicine, in 1587. The text describes hundreds of distinct herbs and thousands of combinations useful for treating disease and alleviating symptoms (Figure 2.1(c)).7

Figure 2.1 (a) Cuneiform clay tablets unearthed from the library of King Ashurbanipal at Nineveh describe Mesopotamian medical practices. It is estimated that they originated between 1900 and 1700 BC. (Image from The Schoyen Collection, MS2670, http://www.schoyencollection.com/smallercollect_files/ms2670.jpg.). (b) A section of the Ebers Papyrus, a compilation of Egyptian medical knowledge composed around 1550 BC containing over 800 prescriptions for various conditions (Image from the NIH U.S. National Library of Medicine Archives, http://www.nlm.nih.gov/archive/20120918/hmd/breath/breath_exhibit/MindBodySpirit/IIBa18.html.). (c) A page from the Pen-tsao Kang-mu, a compilation of traditional Chinese medicines written by Li Shih-chen. The completed text contains over 1800 Chinese medicines and 11,000 prescriptions (Image from the U.S. National Library of Medicine, History of Medicine Division http://www.nlm.nih.gov/exhibition/chinesemedicine/images/017c.jpg.).

There are some commons threads that run through all preindustrial drug discovery efforts, irrespective of their country or region of origin. First, they depended almost exclusively on plants, plant-derived mixtures, or plant extracts, as the ability of preindustrial society to isolate or prepare pure chemicals with medicinal value was limited. Second, medications developed in the preindustrial ages were identified using empirical observation of the presence or absence of symptoms in patients, rather than an understanding of the disease or condition afflicting the patient. Third, and perhaps most importantly, all of the efforts to develop new medication in the preindustrial age of drug discovery did so in the absence of the vast majority of the fundamental knowledge required to understand even the basic principles of disease progression. This almost certainly led to the use of any number of concoctions with little true medicinal value and some that were actually detrimental to the patients’ well-being.

Despite these facts, there are a number of medications that were identified prior to the advent of modern drug discovery that still play an important role in modern medicine. The treatment of malaria caused by Plasmodium falciparum, for example, was revolutionized by the discovery of quinine, an alkaloid found in cinchona bark (Figure 2.2). Agostino Salumbrino (1561–1642), a Jesuit living in Lima, Peru, observed the Quechua people chewing the bark from the cinchona tree in an effort to relieve shivering and fevers. Although Salumbrino certainly had no knowledge of the causative malaria parasite, he did recognize that the symptoms of the febrile phase of malaria might be positively impacted by the cinchona bark and arranged for a sample to be shipped to Rome for evaluation as a treatment for malaria. The cinchona bark, also known as Jesuit’s bark or Peruvian bark, and the Quechua people thus became the source of the first successful antimalarial agent, a drug that was a first line treatment for malaria infection until 2006.8

Figure 2.2 The cinchona tree (left) and quinine (right) were important players in the treatment of malaria infection for over 300years. Source: http://upload.wikimedia.org/wikipedia/commons/e/e8/Koeh-179-cropped.jpg.

In a similar fashion,...