Synthesis of a Novel Suppressor of β-Cell Apoptosis via Diversity-Oriented Synthesis

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 SNAr cycloetherification of a linear amine template to afford eight stereoisomeric eight-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 BRD0476 (probe ML187), which had an approximately 3-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.