Small Molecule Disruptors of the Glucokinase鈥揋lucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

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• 作者：Nuria A. Tamayo ; Mark H. Norman ; Michael D. Bartberger ; Fang-Tsao Hong ; Yunxin Bo ; Longbin Liu ; Nobuko Nishimura ; Kevin C. Yang ; Seifu Tadesse ; Christopher Fotsch ; Jie Chen ; Samer Chmait ; Rod Cupples ; Clarence Hale ; Steven R. Jordan ; David J. Lloyd ; Glenn Sivits ; Gwyneth Van ; David J. St. Jean ; Jr.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4462-4482
• 全文大小：1041K
• ISSN：1520-4804

文摘

The glucokinase鈥揼lucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure鈥揳ctivity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.