Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

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• 作者：David J. St. Jean ; Jr. ; Kate S. Ashton ; Michael D. Bartberger ; Jie Chen ; Samer Chmait ; Rod Cupples ; Elizabeth Galbreath ; Joan Helmering ; Fang-Tsao Hong ; Steven R. Jordan ; Longbin Liu ; Roxanne K. Kunz ; Klaus Michelsen ; Nobuko Nishimura ; Lewis D. Pennington ; Steve F. Poon ; Darren Reid ; Glenn Sivits ; Markian M. Stec ; Seifu Tadesse ; Nuria Tamayo ; Gwyneth Van ; Kevin C. Yang ; Jiandong Zhang ; Mark H. Norman ; Christopher Fotsch ; David J. Lloyd ; Clarence Hale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 23, 2014
• 年：2014
• 卷：57
• 期：2
• 页码：325-338
• 全文大小：638K
• ISSN：1520-4804

文摘

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.