Small Molecule Disruptors of the Glucokinase鈥揋lucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket

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• 作者：Fang-Tsao Hong ; Mark H. Norman ; Kate S. Ashton ; Michael D. Bartberger ; Jie Chen ; Samer Chmait ; Rod Cupples ; Christopher Fotsch ; Steven R. Jordan ; David J. Lloyd ; Glenn Sivits ; Seifu Tadesse ; Clarence Hale ; David J. St. Jean ; Jr.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5949-5964
• 全文大小：690K
• ISSN：1520-4804

文摘

Structure鈥揳ctivity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N鈥?2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase鈥揼lucokinase regulatory protein (GK鈥揋KRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (鈥渟helf region鈥? as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC₅₀ = 0.005 渭M and EC₅₀ = 0.205 渭M, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.