title: Encoded combinatorial chemistry: synthesis and screening of a library of highly functionalized pyrrolidines.
abstract: The application of a new encoding technology for drug discovery is described. 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 structure of which is a record of the specific reagents from which that library member was prepared. After the ligands were solubilized, an array of such beads was screened for angiotensin-converting enzyme inhibitory activity, and the structures of active pyrrolidines were deduced by analysis of the associated tags at sub-picomole levels. Several extremely potent enzyme inhibitors were identified, many from multiple beads. The most potent inhibitor was found to have a Ki of 160 pM, approximately 3-fold more active than captopril in the same assay. Direct comparison with iterative deconvolution shows that the encoded screening strategy is a much more efficient means for extracting information from such compound collections, producing more data on a larger number of active structures.
authors.affiliation: Affymax Research Institute, Santa Clara, CA 95051, USA.
authors.forename: D
authors.initials: D
authors.lastname: Maclean
authors.forename: J R
authors.initials: JR
authors.lastname: Schullek
authors.forename: M M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Ni
authors.forename: E M
authors.initials: EM
authors.lastname: Gordon
authors.forename: M A
authors.initials: MA
authors.lastname: Gallop
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011759:Pyrrolidines