ENCODED COMBINATORIAL CHEMISTRY - SYNTHESIS AND SCREENING OF A LIBRARY OF HIGHLY FUNCTIONALIZED PYRROLIDINES

The application of a new encoding technology for drug discovery is des cribed, A combinatorial library of mercaptoacyl pyrrolidines has been prepared on a beaded polymeric support, Each polymer bead carries one library constituent In association with an oligomeric ''tag,'' the str ucture of which is a record of the specific reagents from which that l ibrary member was prepared, After the ligands were solubilized, an arr ay of such beads was screened for angiotensin-converting enzyme inhibi tory activity, and the structures of active pyrrolidines were deduced by analysis of the associated tags at sub-picomole levels, Several ext remely potent enzyme inhibitors were identified, many from multiple be ads, The most potent inhibitor was found to have a K-i of 160 pM, appr oximate to 3-fold more active than captopril in the same assay, Direct comparison with iterative deconvolution shows that the encoded screen ing strategy is a much more efficient means for extracting information from such compound collections, producing more data on a larger numbe r of active structures.