D. Maclean et al., ENCODED COMBINATORIAL CHEMISTRY - SYNTHESIS AND SCREENING OF A LIBRARY OF HIGHLY FUNCTIONALIZED PYRROLIDINES, Proceedings of the National Academy of Sciences of the United Statesof America, 94(7), 1997, pp. 2805-2810
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.