Encoded combinatorial chemistry: Synthesis and screening of a library of highly functionalized pyrrolidines

Encoded combinatorial chemistry: Synthesis and screening of a library of highly functionalized pyrrolidines

Affymax Research Institute, 3410 Central Expressway, Santa Clara, CA 95051

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 K _i of 160 pM, ≈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.

Footnotes

↵ * To whom reprint requests should be addressed.
Peter G. Schultz, University of California, Berkeley, CA
ABBREVIATIONS:

ACE,

angiotensin-converting enzyme;

Fmoc,

9-fluorenylmethoxycarbonyl;

NMP,

N-methyl pyrrolidine;

BB,

dibutylamine;

PP,

dipentylamine;

HH,

dihexylamine;

OO,

dioctylamine;

O′O′,

bis-(2-ethylhexyl)amine;

MH,

methylhexylamine;

MH′,

methylheptylamine;

MD,

methyldodecylamine;

EB,

ethylbutylamine;

Alloc,

allyloxycarbonyl