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ACS medicinal chemistry letters DOI:10.1021/ml200120m

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

Publication TypeJournal Article
Year of Publication2011
AuthorsChou, DH, Duvall, JR, Gerard, B, Liu, H, Pandya, BA, Suh, BC, Forbeck, EM, Faloon, P, Wagner, BK, Marcaurelle, LA
JournalACS medicinal chemistry letters
Date Published2011/09/08

The 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.