Soluble synthetic combinatorial libraries: The use of molecular diversities for drug discovery

Methods for the Generation and systematic screeninG of immense molecular diversities (i.e., tens to hundreds of millions of compounds) have recently been developed and represent a powerful tool in the search for novel pharmacoloGical aGents [reviewed in (Gallop et al., 1994; Gordon et al., 1994; Blondelle et al., 1995a; Pinilla et al., 1995)]. A number of different strateGies based on the principle of solid phase synthesis are now available to prepare these diversities in a manner which permits their ready use in bioloGical screeninG. The synthesis of libraries was oriGinally focused on peptides and nucleotides, for which synthetic procedures were straiGhtforward and well established. Peptides are Key mediators of biochemical information and have lonG been used as startinG compounds for the development of novel druGs, even thouGh they have limitations as potential therapeutic aGents due to their typical lacK of oral activity, susceptibility to proteolytic breaKdown, and inability to pass throuGh the blood brain barrier. Due to these limitations, recent trends in this field have been directed toward the preparation of chemical libraries as potential sources for improved leads for druG discovery. Powerful chemical methods have been developed which taKe advantaGe of solid phase synthetic procedures for the Generation of a wide ranGe of compounds havinG novel physioloGical properties. Thus, a variety of novel solid phase-based chemistries enable the Generation of libraries of orGanic molecules in an efficient and reproducible manner.