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Synthesis of a novel suppressor of beta-cell apoptosis via diversity-oriented synthesis.
|Publication Type||Journal Article|
|Authors||Chou, DH, Duvall JR, Gerard B., Liu H., Pandya BA, Suh BC, Forbeck EM, Faloon P., Wagner BK, and Marcaurelle LA|
|Abstract||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.|
|Year of Publication||2011|
|Journal||ACS medicinal chemistry letters|
|Date Published (YYYY/MM/DD)||2011/09/08|