Diabetes is a metabolic disorder characterized by high blood glucose levels and affects 8.3% of people in the United States. It is also one of the leading causes of death in the U.S. In type-1 diabetes (T1D), autoimmune destruction of pancreatic beta cells leads to lowered production of insulin, an essential hormone for the regulation of glucose.
To discover novel therapies for T1D, our group screened for small molecules that inhibit immune-mediated death of ß-cells for the recovery of insulin levels. BRD0476, a small molecule developed by diversity-oriented synthesis (DOS), was found to be an effective inhibitor of cytokine-induced beta-cell apoptosis.
In the present study, we describe the design and synthesis of analogs of BRD0476 with the goal of increasing metabolic stability, which is associated with the susceptibility of compounds to undergo biotransformation. Thus, we can select and develop compounds with favorable pharmacokinetic properties. In particular, we describe the design of naphthyl analogs with incorporation of electron-withdrawing groups to prevent oxidative metabolism mediated by CYP450 enzymes.
The development of biologically active analogs of BRD0476 that are metabolically stable may prove to be a novel intervention for the treatment of T1D.
PROJECT: Development of small-molecule inhibitors of cytokine-induced ß-cell apoptosis with improved metabolic stability
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