Summary And Conclusions

Combinatorial chemistry and multiple parallel syntheses have transformed the field of medicinal chemistry for the better. The last decade has seen a revitalization and much dramatically useful technology has been discovered. No laboratory seriously involved in the search for new therapeutic agents can afford not to employ this technology.

From the vantage point of 2002, one can now look back at what has been done in the amazingly short time that this technique has been widely explored and one can see some things more clearly now and use the methodology more cunningly.

In the heady early days of combinatorial chemistry one frequently heard the opinion that existing drugs were only those to which nature or good fortune had laid a clear path. Some believed that there were large numbers cf underexplored structural types that could be drugs if only they were prepared and screened. Combichem promised to make this a reality. It would be nice, indeed, if this had turned out to be true! It cannot be denied that there is some justice in this belief; speculative synthesis continues to reveal important drugs. Nonetheless, the cruel restraints that ADME and toxicity considerations place on our chemical imagination have ruined this dream of easy and unlimited progress. The present wedding of combichem with medicinal chemical knowledge is extremely powerful, and we no longer in the main waste time on collections of molecules that have no chance of becoming drugs. Clearly space for chemical diversity is larger than space for medicinal diversity.

BC (before combichem) there was little motivation for enhanced speed of synthesis. Generally, synthesis could be accomplished much more quickly than screening and evaluation of the products. Enhanced speed of construction simply produced a greater backlog of work to be done. The advent of high-through put screening in the 1980s changed all this. The backlogs emptied rapidly, and there was a demand for more compounds. In addition, new firms were founded to take advantage of newer screening methodologies. These firms had no retained chemical libraries to screen and larger firms were reluctant to allow their libraries to be screened by outsiders. A significant part of these needs were met by the methods in this chapter. With synthesis and screening back in phase, the next choke point in the pipeline has become animal testing, toxicity, solubility, and penetrability. These factors are presently under intensive examination in attempts to elucidate these properties in a similarly rapid fashion or to predict them so that favorable characteristics can be designed into chemical library members from the outset and thus largely avoid having to deal with them. It can readily be seen that further choke points lie distally in the pipeline and these will have to be dealt with in turn. Some time can be saved by speeding things along the way and also by dealing with the remaining constrictions in parallel rather than simultaneously, but it is difficult to see how they can all be resolved in a rapid manner. Fortunately the flow through the pipeline diminishes through increasing failure of leads to qualify for further advancement and this is helpful in reducing the magnitude of the job but the problems remaining will still be vexing. Part of the difficulty is that certain biological phenomena cannot be hurried. For example, no matter how much money and effort one is willing to throw at the problem, producing a baby requires essentially 9 months from conception. Hiring nine women will not result in producing a baby in 1 month. The problem in shortening drug seeking is further compounded in that the problem is not akin to brick laying. To produce a brick wall of a given dimensions more quickly is largely a matter of buying the bricks and hiring and motivating enough skilled labor. In drug seeking, one has to design the bricks first and develop the technology. Combichem does speed the process along but does not remove the elements of uncertainty that must be overcome. Given the strictures placed on clinical studies and their solidification in law and custom, it is hard to see how this phase of the drug seeking sequence can be shortened through chemical effort.

High-throughput screening can be likened to hastening the process of finding a needle in a haystack. Combinatorial chemistry can be likened to the preparation of needles. Ideally one should strive to make a few more useful needles embedded in progressively smaller haystacks. This involves mating as well as is possible productive chemical characteristics with productive biological properties. Combinatorial chemistry and multiple parallel synthesis in the hands of the skillful and lucky chemist rapidly zeros in on the best combination of atoms for a given purpose. This chemist receives approbation for his/her efforts. Those who consistently come up with useless compounds will eventually be encouraged to find other work.

There has been a dramatic increase in investment in drug discovery during the last decade (estimated at 10% annually). Unfortunately this has yet to result in a burst of new introductions. Certainly chemical novelty has largely given way to potential use. Diversity no longer rules. This is perhaps the combinatorial chemist's equivalent of the businessman's mantra that whereas efficiency is doing things properly, effectiveness is doing proper things. As with much of the points being discussed, achieving a proper balance is essential.

It is interesting to note also that a 100-fold increase in screening activity has not yet resulted in a corresponding increase in the introduction of new pharmaceuticals. Part of the explanation for this is that ease of synthesis does not necessarily equate to equivalent value of the products. If each compound in chemical libraries was carefully designed and the data therefrom carefully analyzed, then the disparity would be smaller than the present experience produces. Another exculpatory factor is that much of the low hanging fruit has already been harvested and the remaining diseases are more chronic than acute and are much more complex in their etiology.

Despite all of these considerations, drug seeking is an exciting enterprise calling for the best of our talents and the appropriate use of high speed synthetic methods gives us a powerful new tool to use.

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