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Synthesis of a novel suppressor of beta-cell apoptosis via diversity-oriented synthesis.

Publication TypeJournal Article
AuthorsChou, DH, Duvall JR, Gerard B., Liu H., Pandya BA, Suh BC, Forbeck EM, Faloon P., Wagner BK, and Marcaurelle LA
AbstractThe synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD-0476 (probe ML187), which had an approximately three-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening, and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.
Year of Publication2011
JournalACS medicinal chemistry letters
Volume2
Issue9
Pages698-702
Date Published (YYYY/MM/DD)2011/09/08
DOI10.1021/ml200120m
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/21927648?dopt=Abstract