Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia
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- 作者：Benjamin D. Stevens ; John Litchfield ; Jeffrey A. Pfefferkorn ; Karen Atkinson ; Christian Perreault ; Paul Amor ; Kevin Bahnck ; Martin A. Berliner ; Jessica Calloway ; Anthony Carlo ; David R. Derksen ; Kevin J. Filipski ; Mike Gumkowski ; Charanjeet Jassal ; Margit MacDougall ; Brendan Murphy ; Paul Nkansah ; John Pettersen ; Charles Rotter ; Yan Zhang ; et al.
- 关键词：Glucokinase ; Hepatoselective ; Allosteric ; OATP ; Diabetes
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：15 December, 2013
- 年：2013
- 卷：23
- 期：24
- 页码：6588-6592
- 全文大小：608 K
文摘
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.