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

Huang, Zhihong and Molteni, Valentina and Liu, Yahu and Hao, Xueshi and Baaten, Janine and Hill, Robert and Meeusen, Shelly and Zou, Yefen and Yan, Shanshan and Jia, Yong and Tremblay, Matthew and Wu, Tom Y.-H. and Ding, Qiang and Liu, Bo and Nguyen-Tran, Van and Shen, Weijun and Bhat, Ganesh and Glynne, Richard and Laffitte, Bryan and Jing, Li (2019) Discovery of 5-(3,4-Difluorophenyl)-3-(pyrazol-4-yl)-7-azaindole (GNF3809) for β-Cell Survival in Type 1 Diabetes. ACS Omega, 4. pp. 3571-3581.

Abstract

Pancreatic β-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 β-cells from cytokine-induced stress should have an impact on maintaining functional β-cell mass in T1D. Screening of a ∼2 million-compound library identified a series of 7-azaindole derivatives as capable of protecting rat insulinoma β-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 β-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.

Item Type: Article
Date Deposited: 02 Mar 2019 00:45
Last Modified: 02 Mar 2019 00:45
URI: https://oak.novartis.com/id/eprint/37797

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