Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif
详细信息 查看全文
- 作者：Kevin J. Filipski ; Angel Guzman-Perez ; Jianwei Bian ; Christian Perreault ; Gary E. Aspnes ; Mary T. Didiuk ; Robert L. Dow ; Richard F. Hank ; Christopher S. Jones ; Robert J. Maguire ; Meihua Tu ; Dongxiang Zeng ; Shenping Liu ; John D. Knafels ; John Litchfield ; Karen Atkinson ; David R. Derksen ; Francis Bourbonais ; Ketan S. Gajiwala ; Michael Hickey ; et al.
- 关键词：Glucokinase activator ; Type 2 diabetes mellitus ; Pyrimidone
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 August, 2013
- 年：2013
- 卷：23
- 期：16
- 页码：4571-4578
- 全文大小：3407 K
文摘
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.