A patent review of glucokinase activators and disruptors of the glucokinase - glucokinase regulatory protein interaction: 2011-2014

被引:33
|
作者
Filipski, Kevin J. [1 ]
Pfefferkorn, Jeffrey A. [1 ]
机构
[1] Pfizer Worldwide Res & Dev, Cardiovasc Metab & Endocrine Dis Chem, Cambridge, MA 02139 USA
关键词
glucokinase; glucokinase activator; glucokinase regulatory protein; TYPE-2; DIABETES-MELLITUS; SMALL-MOLECULE DISRUPTORS; HEPATIC GLUCOKINASE; CLINICAL CANDIDATE; ALLOSTERIC ACTIVATORS; SCALABLE SYNTHESIS; EUGLYCEMIC CLAMP; GLUCOSE; DISCOVERY; AZD1656;
D O I
10.1517/13543776.2014.918957
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Introduction: Glucokinase (GK) is a key regulator of glucose homeostasis, and development of small molecule activators of this enzyme represents a promising new approach for the treatment of type 2 diabetes mellitus. Areas covered: This manuscript reviews small molecule patent disclosures between late 2011 and February 2014 for both GK activators (GKAs) and GK-glucokinase regulatory protein (GK-GKRP) disruptors. The review is organized by company and structural class. Expert opinion: The field of GKA research continues to progress, driven by research across many organizations. To date, > 20 candidates have entered clinical development with the most advanced in Phase II trials. Despite promising efficacy, a significant number of early candidates have been discontinued for various reasons including increased risk of hypoglycemia and lack of durability. Recent work in the field has focused on liver-selective activators, which have shown lower hypoglycemia risk, including the development of novel GK-GKRP disruptors that act to indirectly increase hepatic GK activity.
引用
收藏
页码:875 / 891
页数:17
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