Introduction-The use of synthetic oligonucleotide ligands, designed to sequence-specifically bind by Watson-Crick base pair recognition to RNA receptors, is a relatively new drug discovery paradigm. This approach, referred to as antisense technology, began to receive considerable drug discovery efforts about nine years ago, primarily by several new biotechnology companies. Phosphorothioate oligodeoxynucleotides (PSs), developed as first generation antisense agents, have been shown to operate by this novel drug mechanism and several PSs have progressed to late stage clinical development. Considerable knowledge has been amassed concerning the pharmacology, pharmacokinetic and toxicology properties of these first generation antisense oligonucleotides, and along with this, certain limitations of PSs as antisense agents have emerged. Structural changes are required to overcome these limitations and to continually improve this novel oligonucleotide drug class.

Although many types of modifications, at essentially all available positions that do not directly interfere with Watson-Crick base pair recognition, have been examined, only 2'-modifications have demonstrated sufficiently interesting drug properties to be moved into advanced studies (1). Indeed, the first, second generation modified oligonucleotides, 2'-O-methy (2) and 2'-O-methoxyethyl (3) gapmers have just recently entered clinical trials for CMV retinitis in AIDS patients. This chapter will briefly discuss the advantages and limitations of the phosphorothioate oligonucleotides as antisense drug candidates. It will then briefly summerize the 2'-modified class of oligonucleotide that address PS limitations. This particular class of second generation modifications, on the basis of impressive, positive pharmacology, pharmacokinetics, and toxicity data in animals, is expected to eventually replace first generation PS antisense oligonucleotides as drug candidates. A number of general reviews, primarily focusing on antisense oligonucleotide medicinal chemistry have periodically been published (1). In particular, three Annual Reports in Medicinal Chemistry have specifically discussed antisense technology (4-6).