Drug discovery is one of the most crucial components of the pharmaceutical industry's Research and Development (R&D) process and is the essential first step in the generation of any robust, innovative drug pipeline. Drug candidate pipelines are usually aimed at disease areas with high unmet medical need where the commercial reward for delivering first in class and/or best in class therapies can be enormous. The R&D process is an extremely lengthy, complex, and strongly regulated activity that has increasing attrition rates and escalating costs (1, 2).

The last 5 years has witnessed a dramatic change in the landscape for the pharmaceutical industry. Consolidation in the market place resulting from a series of megamergers has created bigger than ever R&D budgets along with matching expectations and goals for increased productivity and growth (1, 2). Just keeping pace with double digit annual growth rates requires each of the top 10 pharmaceutical companies to launch at least five significant new chemical entities (NCEs) per year with blockbuster potential (greater than $500 million/year). However, this goal is set against a historical track record of less than one NCE per year, per company, of which less than 10% reached sales of greater than $350 million (1, 2). Additionally, in an ambitious attempt to exploit the maximum life of drug patents, companies have also set challenging goals in reducing overall drug development time to market.

An ever increasing regulatory burden and strong emphasis on drug safety ensures a series of extremely tough hurdles before any increased flow of drugs works its way through the industry's pipelines onto the market. Those companies that find the quickest way to put the first and best in class products on the market in a cost-efficient way will become the clear commercial winners in such a competi

4.2 Miniaturization of Screening Assays, 66 5 Summary, 67

tive arena. The drive to have more innovative and safer drugs on the market, quicker than ever before, has fueled enormous interest in different ways of revolutionizing the process by which drug discovery and development is carried out. This can be most clearly seen in the upstream phase of the R&D process starting from target discovery through early pre-clinical testing.

From penicillin in 1929 (3) to the ^-blockers and 5-hydroxytryptamine (5HT) antagonists of the 1970s (4), pharmaceutical companies have relied on a mix of "accidental" serendipitous discovery, inspired scientific insight, and incremental progression in chemistry to develop drugs.

However, the promise of major improvements in productivity, cost efficiency, and speed of discovery has created radical changes in the way drug discovery is carried out. Leading this wave of change has been the development and implementation of a series of innovative, state-of-the-art technologies aimed at the early lead discovery process.

It is in this area that the overall impact of technological advances in genomics, combinatorial chemistry, compound management, computer-aided drug design (CADD), high-throughput screening (HTS), and bioinfonnatics has created a new drug discovery paradigm.

In this chapter, we will describe the history and process of lead discovery from initial target identification and disease validation through the lead identification process itself, culminating in lead optimization and pre-clin-ical candidate selection. The full range of technologies and approaches that have been brought to bear on this complex activity will also be highlighted.

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