Small Molecule Disruptors of the Glucokinase鈥揋lucokinase Regulatory Protein Interaction: 3. Structure鈥揂ctivity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N鈥?a

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• 作者：Nobuko Nishimura ; Mark H. Norman ; Longbin Liu ; Kevin C. Yang ; Kate S. Ashton ; Michael D. Bartberger ; Samer Chmait ; Jie Chen ; Rod Cupples ; Christopher Fotsch ; Joan Helmering ; Steven R. Jordan ; Roxanne K. Kunz ; Lewis D. Pennington ; Steve F. Poon ; Aaron Siegmund ; Glenn Sivits ; David J. Lloyd ; Clarence Hale ; David J. St. Jean ; Jr.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 10, 2014
• 年：2014
• 卷：57
• 期：7
• 页码：3094-3116
• 全文大小：884K
• 年卷期：v.57,no.7(April 10, 2014)
• ISSN：1520-4804

文摘

We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK鈥揋KRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).