Obtaining a better understanding of the important factors in molecular recognition in conjunction with developing potent new therapeutic agents is a major focus of scientific research. Very powerful chemical and biological methods have recently been developed for the construction of large combinatorial libraries of peptides and oligonucleotides which are then screened against a specific receptor or enzyme in order to determine the key molecular recognition elements of the biopolymer for that receptor or enzyme. Unfortunately, peptides and oligonucleotides have very poor oral activities and rapid clearing times and thus have limited utility as bioavailable therapeutic agents. While virtually any therapeutically interesting compound can be synthesized, these compounds are currently synthesized one at a time, thus dramatically limiting the number of compounds which can be evaluated. This limitation could be overcome by developing the methodology for the combinatorial synthesis of large numbers of derivatives of therapeutically important classes of bioavailable organic compounds. Screening these compounds against key receptors or enzymes would then greatly accelerate the acquisition of useful structure versus recognition data and would revolutionize the search for potent new therapeutic agents.
The specific aim of this proposal is to develop approaches for the combinatorial synthesis of large libraries of derivatives of two therapeutically important classes of organic compounds; 1 ,4- benzodiazepines which are one of the most prescribed classes of therapeutic agents and target diverse receptors and enzymes, and prostaglandins, for which both the natural and unnatural derivatives modulate a wide spectrum of physiological activities. In order to accomplish this goal, general solid-phase synthesis methodology is first being developed to construct the derivatives on solid support; when synthesis on solid support proceeds in sufficiently high yield, purification and isolation steps can be eliminated thus dramatically increasing synthesis efficiency. After construction of the combinatorial libraries, screening will be performed to identify potent new therapeutic agents. In particular, the 1,4-benzodiazepine library will be screened to identify potent cholecystokinin antagonists as well as potent and specific inhibitors of tyrosine receptor kinases which are important targets for cancer therapy.
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