chapter  1
6 Pages

Combinatorial Chemistry and Combinatorial Technologies: Principles and Applications Giorgio Fassina and Stanislav Miertus

The time and cost needed for the development of new drugs have increased steadily during the past three decades. Estimated costs for introducing a new drug in the market now reach around $200-300 million U.S., and this process takes around 10-12 years after discovery. This increase in time and cost is mainly due to the extensive clinical studies of new chemical entities required by competent regulatory agencies, such as the U.S. Food and Drug Administration (FDA) and, to a lesser extent, to the increased costs associated with research. The time and cost required for clinical and preclinical evaluation of new drugs is not likely to decrease in the near future and, as a consequence, a key issue for pharmaceutical companies to stay in the market has been to increase the number of new drugs in the development pipeline. Drug discovery in the past has been based traditionally on the random screening of collections of chemically synthesized compounds, or extracts, derived from natural sources, such as microorganisms, bacteria, fungi, and plants, of terrestrial or marine origin, or by modifications of chemicals with known physiological activities. This approach has resulted in many important drugs, but the ratio of novel to previously discovered compounds has diminished with time. In addition, this process is very time consuming and expensive. A limiting factor was the restricted number of molecules available, or extract samples to be screened, since the success rate in obtaining useful lead candidates depends directly on the number of samples tested. Chemical synthesis of new chemical entities often is a very laborious task, and additional time is required for purification and chemical characterization. The average cost of creating a new molecular entity in a pharmaceutical company is around $7500 U.S./ compound [1]. Generation of natural extracts, while very often providing interesting new molecular structures endowed with biological

properties, leads to mixtures of different compounds at different concentrations, thus making activity comparisons very difficult. In addition, once activity is found in a specific assay, the extract needs to be fractionated in order to identify the active component. Quite often, the chemical synthesis of natural compounds is extremely difficult, thus making the lead development into a new drug a very complex task. While the pharmaceutical industry was demanding more rapid and cost-effective approaches to lead discovery, the advent of new methodologies in molecular biology, biochemistry, and genetics, leading to the identification and production of an ever-increasing number of enzymes, proteins, and receptors involved in biological processes of pharmacological relevance, and good candidates for the development of screening assays, complicated this scenario even more. The introduction of combinatorial technologies provided an unlimited source of new compounds, capable of satisfying all these needs. This approach was so appealing and full of promise that many small companies started to flourish, financed by capital raised from private investors. Once combinatorial technologies clearly demonstrated the potential to identify new leads with a previously unknown speed, the majority of these companies were purchased by big pharmaceutical companies. Combinatorial approaches were originally based on the premise that the probability of finding a molecule in a random screening process is proportional to the number of molecules subjected to the screening process. In its earliest expression, the primary objective of combinatorial chemistry focused on the simultaneous generation of large numbers of molecules and on the simultaneous screening of their activity. Following this approach, the success rate of identifying new leads is greatly enhanced, while the time required is considerably reduced.