Discovery of 5-(3,4-Difluorophenyl)-3-(pyrazol-4-yl)-7-azaindole (GNF3809) for beta-Cell Survival in Type 1 Diabetes

Pancreatic beta-cell apoptosis, a hallmark of the development of type 1 diabetes (T1D), is associated with increased levels of pro-inflammatory cytokines. Thus, an agent protecting beta-cells from cytokine-induced stress should have an impact on maintaining functional beta-cell mass in T1D. Screening of a similar to 2 million-compound library identified a series of 7-azaindole derivatives as capable of protecting rat insulinoma beta-cells from death induced by pro-inflammatory cytokines. The screening hits were optimized to result in GNF3809, a compound which preserves insulin content and viability of beta-cells in both rodent and human islets under stress induced by cytokines. In vivo, orally bioavailable GNF3809 prevented elevated blood glucose level and improved oral glucose tolerance in a nonobese diabetic mouse model. This work lays the foundation for development of a new class of therapeutic interventions for T1D.