26] Synthesis and evaluation of 1,4-benzodiazepine libraries

Abstract

Publisher Summary One of the initial steps in the development of therapeutic agents is the identification of lead compounds that bind to the receptor or enzyme target of interest. Many analogs of the lead compounds are then synthesized to define the key recognition elements for maximal activity. In general, many compounds must be evaluated in both lead identification and optimization steps. Recently, the demand for compounds for drug discovery efforts has increased dramatically. This is due in large part to the technological advances in screening procedures, for many therapeutic targets, that allow for the rapid and efficient evaluation of thousands to millions of compounds. To address this demand, very powerful chemical and biological methods have been developed for the generation of large combinatorial libraries of peptides and oligonucleotides that are then screened against a receptor or enzyme to identify the high-affinity ligands or potent inhibitors, respectively. Because of the broad biological activity and desirable pharmacokinetics of 1,4-benzodiazepine derivatives, general and expedient solid-phase synthesis methods have been developd for this class of molecules. This chapter describes the methods used for the design and simultaneous synthesis of a library of 11,200 structurally diverse benzodiazepine derivatives that incorporate a wide variety of chemical functionality.