Combinatorial chemistry grew out of peptide chemistry and initially served the needs of biochemists and the subset of medicinal chemists who specialized in peptide science. Its first decade or so concentrated on oligopeptides and related molecules. It continued to evolve, however, and now permeates virtually every corner of medicinal chemistry and a major effort is underway to discover new, orally active, pharmaceuticals using these methods.

Many will agree that the path leading to the present state of combinatorial chemistry essentially started with thesolid phase synthetic experiments on peptides by Bruce Merrifield in 1962 (1, 2). This work had immediate impact, facilitated in large part because of the essentially iterative reactions, to completion by use of reagents in excess, its susceptibility to automation, and the ease of removing detritus from the products by simple washing and filtration away from the resins. At first this extremely useful technology was employed in a linear fashion. It was probably Furka in Hungary a decade or so later who realized that the methodology could lead to simultaneous synthesis of large collections of peptides and conceived of the mix and split methods (3). Geyson made the whole process technically simpler in 1984 and produced large scale compound collections of peptides (4) and Houghton introduced "tea bag" methodologies in 1985 in which porous bags of resins were suspended in reagents (5). Comparatively few organic chemists undertook the preparation of ordinary organic substances on solid phases because the work is rather more complex when applied to non-oligomeric substances caused by greater variety of reactants and conditions required, and this work at first failed to develop a significant following. Solid phase organic chemistry was also comparatively underdeveloped and this held back the field. This changed in dramatic fashion after the publication of Bunin and Ellman's seminal work on solid phase organic synthesis (SPOS) of arrays of l,4-benzodiazepine-2-onesin 1992 (6).Soon other laboratories published related work on this ring system, and work on other drug-like molecules followed in rapid order and the race was on. In the initial phases, solid phase or-

gaiiic synthesis predominated, and this persisted until about 1995, when solution phase combinatorial chemistry began to make serious inroads. Until about 1997, roughly one-half of the libraries reported were either of peptides or peptidomimetics. Subsequently libraries of drug-like small molecules have become increasingly popular.

The work on combinatorial libraries has inspired the rapid development of a wide variety cf auxiliary techniques including the use of reagents on solid support, capture resins, chemical and biological analysis of compound tethered to resins, informatics to deal with the huge volume of structural and biological data generated, the synthesis of a wide variety of peptide-like and heterocyclic systems hitherto prepared solely in solution, photolithographic techniques allowing the production of geographically addressed arrays on a "credit card," preparation of gene array chips, attachment of coding sequences, use of robotics, and the preparation of oligonucleotides by Lets-inger in 1975 (7) and of oligosaccharides by Hindsgaul in the 1990s (8). At this moment several thousand papers are appearing each year describing the preparation and properties of compound libraries either in mixtures or as individual substances. Several books (935) and reviews (36-49) are available for the interested reader. Those of Dolle are particularly recommended because he has undertaken the heroic task of organizing and summarizing each year the world's literature on the topic. That of Thompson and Ellman is especially thorough in reviewing the literature up until 1996 from a chemical viewpoint. A great many other reviews are available, including many in slick-cover free journals that arrive on our desks weekly. In addition to these, at least three specialist journals have been established in the area. These are the Journal of Combinatorial Chemistry, Molecular Diversity, and Combinatorial Chemistry and High Throughput Screening.

Another important factor leading to the explosion of interest in combinatorial chemical techniques was the development of small firms devoted to the exploitation of genetic discoveries through development of high-throughput screening methods. These firms by and large did not have libraries of com pounds to put through these screens and were seeking collections of molecules. Combinatorial chemistry addressed these needs. When these methods were taken up by big pharmaceutical companies, existing libraries quickly proved inadequate for the need and combinatorial methodologies clearly addressed this need as well. Just about 10 years after these seminal events, the face of medicinal chemistry has been irretrievably altered. While combinatorial chemistry has in some respects not lived up to the initial hopes, its value is firmly established and no serious firm today fails to use these methods. By the year 2002, well over 1000 libraries have been reported. Many of these include reports of the biological activity of their contents. This is remarkable considering that the field is scarcely more than a decade old!

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