Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (nN → σ*S–X) Interaction fo
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- 作者：Lewis D. Pennington ; Michael D. Bartberger ; Michael D. Croghan ; Kristin L. Andrews ; Kate S. Ashton ; Matthew P. Bourbeau ; Jie Chen ; Samer Chmait ; Rod Cupples ; Christopher Fotsch ; Joan Helmering ; Fang-Tsao Hong ; Randall W. Hungate ; Steven R. Jordan ; Ke Kong ; Longbin Liu ; Klaus Michelsen ; Carolyn Moyer ; Nobuko Nishimura ; Mark H. Norman ; Andreas Reichelt ; Aaron C. Siegmund ; Glenn Sivits ; Seifu Tadesse ; Christopher M. Tegley ; Gwyneth Van ; Kevin C. Yang ; Guomin Yao ; Jiandong Zhang ; David J. Lloyd ; Clarence Hale ; David J. St. Jean Jr.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：December 24, 2015
- 年：2015
- 卷：58
- 期：24
- 页码：9663-9679
- 全文大小：744K
- ISSN：1520-4804
文摘
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK–hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK–hGKRP IC50 = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ*S–X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = ?45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK–GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.