The Impact of High Throughput Organic Synthesis
on R&D in Bio-Based Industries
John P. Devlin
ARRT International, Inc.
P.O. Box 1838
New Milford, CT 06776
The pharmaceutical industry has passed through a remarkable transition in the past decade in its effort to identify novel compounds that interact with control aspects of new molecular targets and to pave the way to new therapeutic agents and product lines. The impact was first apparent in the biological sphere as assays reached the micro level and automation permitted sample throughput in multiple screens that a few years earlier was unimaginable. High Throughput Screening (HTS) was born and quickly adopted as an important, if not the only, source of the initial "hits" required for the generation of leads for commercial development. The agrochemical industry has followed a similar path.
The importance and permanence of the HTS focus has been manifest within the organizational structure of most corporations. Such structures tend to be immovable and only bend when economic considerations surface at both the operational and futures levels. HTS is such an event. Discovery has shifted from a closed chemist/biologist relationship into a complex multidisciplinary cell that has generated a new level of professionalism within the industry.
Compound Management alone constitutes new positions and occasionally departments in larger organizations. This function controls the fodder that HTS requires and essentially hold the key to the success of the discovery program. It also provides for the assessment and management of diversity from within the corporate archives or in the analysis of external offerings through time-honored manual techniques or the use of software packages from companies such as Tripos, MDL Information Systems or Chemical Design.
Each compound within a company's archives ultimately finds its origin in the labors of one or more chemists in synthesis or the isolation and identification of natural products. The cost for the preparation of such compounds on a single compound basis are substantial. Each requires the attention of 1 PhD-chemist with one or two assistants at an operational cost basis of $50,000 per month. The resulting numbers are illustrated here in comparison to the two primary modes of automated synthesis (Table 1).
Synthesis Costs and Returns
|System||Cmpds per Lab/Month||Cost/Cmpd (US $)||Yield (mgms)||Application|
|Single Preps||5 - 10||5,000 - 10,000||1 - 10,000||Specifics|
|Modular||50 - 100||500 - 1,000||20 - 80||Development|
|Microplate||500 - 1,000||50 - 100||2 - 8||Screening|
The equity resident in the archives of a large company is therefore substantial. The success of HTS in uncovering the unknown parameters of a new receptor site, however, relies on access to a collection of compounds that possesses a very broad range of chemical functional groups dispersed in 3-D space in diverse structural frameworks. This level of diversity is rarely found in a company's archives. The development of most corporate collections has relied on acquisition from external sources. Initially, such access was primarily from universities and research institutes worldwide. The fragmentary nature of these resources spawned the creation of small industries, the compound brokers, that have served as gophers and data processors in the collection and marketing of such compounds. It is economically preferable for industrial groups to use these brokers and avoid the need and expense of scouring the multitude of academic archives. A significant savings over that of in-house synthesis is realized, however, the number required to come close to reasonable diversity brings the required investment again to a substantial level. The average cost of $50 per sample places the overall expenditure for 100,000 compounds at $5,000,000 plus handling, storage and maintenance costs. While this value can be reduced with rigorous negotiation when large numbers are purchased, the better bargain is to purchase compounds pre-plated in 96-well microplates -- a 70% savings (based on current pricing from MicroSource Discovery Systems, Gaylordsville, CT). The micro requirements of most HTS assays (<10 micrograms) makes this latter approach especially attractive to small companies wherein acquisition and management costs of a large compound collection are prohibitive.
All of these external resources have relied heavily on the university as a primary source. An unfortunate consequence of these activities over the past decade has been a depletion of the academic resources that have accumulated over the past fifty years. Furthermore, the availability of useful quantities from current academic research has become less likely as modern chemical techniques and instrumentation permit studies with only a few milligrams ... not a lot left over for commercial programs. This is especially apparent in the natural product field, as the unique diversity inherent in that group has placed such acquisition at a premium.
Market demands, nevertheless, persist and have led to the emergence of synthesis factories, primarily in eastern Europe, that prepare compounds specifically for the screening market using conventional chemical techniques. Output has been greatly enhanced at some of these centers by adoption of modular approaches in synthesis. These sources have helped to fill the void in numbers but have done little to enhance the level of structural diversity or the cost factor.
Chemists have addressed the sample resource question directly. The first approach was in the use of solid and solution phase techniques in the synthesis of large libraries of peptides through combinatorial chemistry. Many discovery-based industries implemented in-house programs in combinatorial chemistry initially to explore the peptide as a supplement to their screening resources, but more recently in the use of the same technologies for the automation of general organic synthesis as the limits and flexibility of the peptide backbone failed to satisfy the more general structural needs of discovery. The success of this approach has led to the generation of a new chemical discipline, High Throughput Organic Synthesis (HTOS), the implementation of such programs as core technologies in many industries, and the emergence, once more, of new industries. Programs in academia also address this need, the tremendous potential it offers in the enhancement of structural diversity and the intellectual challenge of devising techniques for the tracking of the thousands of compounds generated as they proceed through a bioassay network. New industries, such as Pharmacopeia and ArQule, have emerged within this specialized arena with chemical innovation and custom synthetic schemes that provide access to large chemical libraries that include features of specific interest to their client. The market and discovery impact has been dramatic.
Despite the excitement over the recent advances in HTOS development and the promises of prominent researchers in this area, HTOS cannot alone provide a diverse and sustained compound supply for screening. Today's technologies can achieve in parallel synthesis only the skeletal and functional complexity that is economically available through classical bench techniques; this aspect alone places full diversity outside the scope of HTOS --- natural products still retain a commanding lead. While contributions to the enhancement of the structural diversity of a company's compound resources has, at best, been modest, the impact of HTOS on the economics of new drug development through rapid analog synthesis and the subsequent transposition of shorter development time into extended useful patent life has been dramatic! It is here that the strength of HTOS and its most important impact is felt.
The development of a lead into a product, in the traditional framework, is a stepwise process. The first stage is based on the assessment of synthetic possibilities within the limitations of organic synthesis and available starting materials, the extrapolation of preferred features defined by precedence, any SAR information, and guides from computational analyses. This has not changed. The next step is the orderly planning of synthesis programs within the structural goals set for the target series, the development of timelines which integrate synthesis with information feedback from primary and secondary bioassay, and further development of the synthetic targets. Analogs of an initial lead can be prepared singly at an average rate of 100 compounds per chemist per year depending on the complexity of the chemistry involved (Table 1). In the traditional mode, the number of chemists employed on a project is defined by management according to the significance of the discovery, the complexity of the syntheses and the intended patent scope ... the primary goal being a critical assessment of market potential and, if justified, the identification of preferred candidates for further development to a marketable product. The subsequent steps involve major capital investment in toxicology and clinical study. Thus, this selection stage is critical to corporate success and, in smaller companies, economic survival.
A reasonable time for candidate selection in the traditional mode has been one to two years. The limiting factor has generally been the initial synthesis stage and the exploration of the numerous parameters associated with SAR development. With the application of HTOS design principles and robotics in organic synthesis, we are seeing this time shortened dramatically! The 1-2 year period for candidate selection can be reduced by as much as 75%. This can constitute an extension in useful patent life by many months. Achieving sales of $1 billion in a new drug market today is not unusual. If we take that value and assess the gain provided by additional time in a protected market, we arrive at an impressive $83 million per month! HTOS can deliver this market advantage.
HTOS has clearly become a new chapter in chemical technology. It brings the excitement of further growth with the resolution of the obvious challenges of conducting chemical synthesis in arrays at semi-micro and sub-micro levels. It also significantly impacts product development in the support industries as new goals are defined in liquid handling, automation and data management. The corollary of this restructuring is the creation of new challenges for the organic chemist, a greater dependence on multidisciplinary interactions, and the internal structure of discovery departments. It has also created new scientific and engineering challenges and product opportunities that permeate support industries. We can look forward to dramatic advances in probing the details of new pharmacophores as HTOS matures into an fully developed industrial technology.
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